Difference between revisions of "Task 7 (MSUD)"

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== HGMD ==
  
== HGMD ==
  +
  +
=== Database facts ===
  +
<span style="color:blue">'''Q'''</span>: What information is given?
  +
  +
'''A''': Only disease causing mutations are included. HGMD lists the following mutation types:
  +
* missense/nonsense
  +
* splicing
  +
* regulatory
  +
* small deletions
  +
* small insertions
  +
* small indels
  +
* gross deletions
  +
* gross insertions/duplications
  +
* complex rearrangements
  +
* repeat variations
  +
For each mutation entry the following information is given in the public version:
  +
* accession number
  +
* codon change
  +
* amino acid change
  +
* codon number
  +
* phenotype
  +
* reference
  +
* comments
  +
  +
<span style="color:blue">'''Q'''</span>: How recent is the release?
  +
  +
'''A''': Release 2013.1 is the current professional version. Entries are made publicly accessible three years after they are included. Mutations that are taken from publicly available locus-specific mutation databases are immediately added to the public version.
  +
  +
<span style="color:blue">'''Q'''</span>: Where does the information come from?
  +
  +
'''A''': The information is extracted from articles that describe genetic diseases. So only published mutations are included.
  +
  +
=== Mutations of BCKDHA ===
  +
  +
The following mutations are listed for BCKDHA (20 June 2013):
  +
  +
{| class="wikitable" border="1" style="width:300px"
  +
! mutation type !! number of mutations
  +
|-
  +
|missense/nonsense ||40
  +
|-
  +
|splicing ||2
  +
|-
  +
|small deletions ||4
  +
|-
  +
|small insertions ||1
  +
|-
  +
|small indels ||1
  +
|-
  +
|gross deletions ||2
  +
|-
  +
|complex rearrangements ||1
  +
|}
  +
  +
  +
All reported mutations are associated with MSUD. Among the 40 mutations of category "missense/nonsense", there are 37 missense mutations listet and 3 nonsense mutations.
  +
  +
Definition of the mutation types:
  +
* missense: single base substitution that leads to amino acid change
  +
* nonsense: single base substitution that leads to a stop codon
  +
* splicing: mutation that affects a splicing side
  +
* small deletion: deletion of few base pairs
  +
* small insertion: insertion of few base pairs
  +
* small indel: insertion / deletion of few base pairs
  +
* gross deletion: deletion of many base pairs
  +
* complex rearrangement: insertion / deletion of many base pairs
   
 
== dbSNP ==
  
== dbSNP ==
  +
  +
[[File:Hist.png|thumb|320px|Histogram of different types of SNPs reported in dbSNP.]]
   
 
=== Database facts ===
  
=== Database facts ===
−
'''Q''': What information is given?
 +
<span style="color:blue">'''Q'''</span>: What information is given?
   
 
'''A''': Short variations in '''nucleotide''' sequence from many different organisms. It contains following information:
  
'''A''': Short variations in '''nucleotide''' sequence from many different organisms. It contains following information:
Line 18: Line 86:
 
** somatic or germline events
  
** somatic or germline events
   
−
'''Q''': How recent is the release?
 +
<span style="color:blue">'''Q'''</span>: How recent is the release?
   
 
'''A''': Current version of dbSNP is build 137. dbSNP web query, ftp data and Entrez Indexing were released on Jun 26, 2012. New release of BLAST database is not yet done. The newest release of BLAST database was released on Nov 14, 2011 from build 135.
  
'''A''': Current version of dbSNP is build 137. dbSNP web query, ftp data and Entrez Indexing were released on Jun 26, 2012. New release of BLAST database is not yet done. The newest release of BLAST database was released on Nov 14, 2011 from build 135.
   
−
'''Q''': Where does the information come from?
 +
<span style="color:blue">'''Q'''</span>: Where does the information come from?
   
−
'''A''': dbSNP is created by the cooperation of the National Human Genome Research Institute and the National Center for Biotechnology Information. It is integrated with the NCBI Genomic data.
 +
'''A''': dbSNP is created by the cooperation of the National Human Genome Research Institute and the National Center for Biotechnology Information. It is integrated with the NCBI Genomic data. There are two sorts of content in dbSNP: submitted and computed data. During a build cycle, submitted SNPs (identified by ss#) which map to the same genomic position, are clustered to a non-redundant set of reference SNPs (refSNPs), that get a unique rs# identifier.
   
 
=== Mutations of BCKDHA ===
  
=== Mutations of BCKDHA ===
  +
  +
Totally 292 SNPs in coding region of BCKDHA were found in dbSNP. 4 mutations are nonsense (stop-gained) which introduce stop condon in the coding region. 152 mutations are missense among which 28 mutations can cause disease. 136 mutations are synonymous codons.
   
 
== SNPdbe ==
  
== SNPdbe ==
   
 
=== Database facts ===
  
=== Database facts ===
−
'''Q''': What information is given?
 +
<span style="color:blue">'''Q'''</span>: What information is given?
   
  +
'''A''': Experimentally annotated effects of non-synonymous SNPs (nsSNP). Computationally annotated structural and functional effects of nsSNP. Association between nsSNP and diseases.
−
'''A''':
 
   
−
'''Q''': How recent is the release?
 +
<span style="color:blue">'''Q'''</span>: How recent is the release?
   
  +
'''A''': The most recent update took place on Mar 05, 2012.
−
'''A''':
 
   
−
'''Q''': Where does the information come from?
 +
<span style="color:blue">'''Q'''</span>: Where does the information come from?
   
  +
'''A''': Experimentally annotated nsSNP from dbSNP; Variants from UniProt and PMD; Genomic data from 1000 Genome collection; predicted impacts on protein structure and function are computed with SNAP and SIFT.
−
'''A''':
  
   
 
=== Mutations of BCKDHA ===
  
=== Mutations of BCKDHA ===
  +
102 SNPs were reported in SNPdbe for BCKDHA. Among them 8 SNPs were reported to have association to MSUD.
   
 
== OMIM ==
  
== OMIM ==
  +
  +
=== Database facts ===
  +
<span style="color:blue">'''Q'''</span>: What information is given?
  +
  +
'''A''': In the allelic variants section of a gene entry, mutations (e. g. substitions or deletions) are given and the phenotype that they are causing. Only selected mutations are listed (see [http://omim.org/help/faq#1.4 OMIM FAQ]), most of which are disease associated.
  +
  +
<span style="color:blue">'''Q'''</span>: How recent is the release?
  +
  +
'''A''': OMIM is updated daily. The entry for BCKDHA was last updated 05/23/2012.
  +
  +
<span style="color:blue">'''Q'''</span>: Where does the information come from?
  +
  +
'''A''': The information comes from published articles. For each mutation the reference article is given in the text of the allelic variants section.
  +
  +
=== Mutations of BCKDHA ===
  +
  +
For BCKDHA, there are 7 missense mutations listed and 2 deletions, where one is a 1-bp (base pair) deletion and the other 8-bp (last update of entry: 05/23/2012). All these mutations are associated with MSUD type IA (classic or intermediate form).
   
 
== SNPedia ==
  
== SNPedia ==
   
  +
=== Database facts ===
−
'''Shen''' TODO
  
  +
<span style="color:blue">'''Q'''</span>: What information is given?
  +
  +
'''A''': The wiki style project 'SNPedia' is open to the internet community. It contains information about effects of SNPs. Annotations from wide range of internet resources such as the dbSNP project, Ensembl or even google search are included into SNPedia. It tries to gather all SNP related information to one web site.
  +
  +
<span style="color:blue">'''Q'''</span>: How recent is the release?
  +
  +
'''A''': Due to contribution of its user community, new updates could occur at any time point. But still it depends on the release of other SNP related resources.
  +
  +
<span style="color:blue">'''Q'''</span>: Where does the information come from?
  +
  +
'''A''': Many different public available databases, resources about SNPs, publications about genomic studies.
  +
  +
=== Mutations of BCKDHA ===
  +
  +
Due the fact that SNPedia is not a database-like data source. Statistics over reported SNPs for BCKDHA is hard to obtain.
  +
  +
== Mutation map ==
  +
  +
102 mutations were selected from different databases. Disease causing mutations are marked in <span style="color: red">'''red'''</span>, mutations that do not cause disease are marked in <span style="color: blue">'''blue'''</span>.
  +
  +
[[File:Mutation-map.png|950px]]
  +
  +
Following table contains the SNPs that we have chosen from different databases:
  +
{| class='wikitable' border='1' style='width:900px'
  +
! Accession.Number !! Codon.number !! Pathogenic !! Mutation !! Type !! pathogenic !! all
  +
|-
  +
| || 17 || N/A || L17F || missense || FALSE || silent
  +
|-
  +
| || 29 || N/A || G29E || missense || FALSE || silent
  +
|-
  +
| rs11549936 || 38 || N/A || P38H || missense || FALSE || silent
  +
|-
  +
| rs80014754 || 38 || N/A || P38P || synonymous-codon || FALSE || silent
  +
|-
  +
| rs150177278 || 41 || N/A || Q41R || missense || FALSE || silent
  +
|-
  +
| || 59 || N/A || A59V || missense || FALSE || silent
  +
|-
  +
| rs149251798 || 61 || N/A || I61M || missense || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM093772 || 69 || Maple syrup urine disease || Q69* || nonsense || TRUE || disease
  +
|-
  +
| rs138025447 || 70 || N/A || N70N || synonymous-codon || FALSE || silent
  +
|-
  +
| rs11549938 || 81 || N/A || M81L || missense || FALSE || silent
  +
|-
  +
| rs148571328 || 95 || N/A || H95H || synonymous-codon || FALSE || silent
  +
|-
  +
| rs11549937 || 96 || N/A || L96L || synonymous-codon || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM005526 || 109 || Maple syrup urine disease || M109T || missense || TRUE || disease
  +
|-
  +
| rs150700696 || 111 || N/A || L111L || synonymous-codon || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM021496 || 125 || Maple syrup urine disease || Q125E || missense || TRUE || disease
  +
|-
  +
| rs139678295 || 126 || N/A || R126W || missense || FALSE || silent
  +
|-
  +
| rs201638798 || 133 || N/A || N133N || synonymous-codon || FALSE || silent
  +
|-
  +
| rs146804716 || 140 || N/A || H140H || synonymous-codon || FALSE || silent
  +
|-
  +
| rs200947033 || 145 || N/A || A145A || synonymous-codon || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM021497 || 151 || Maple syrup urine disease || T151M || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM082498 || 152 || Maple syrup urine disease || D152N || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM930067 || 159 || Maple syrup urine disease || R159W || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM984173 || 166 || Maple syrup urine disease || Y166N || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM984174 || 167 || Maple syrup urine disease || R167Q || missense || TRUE || disease
  +
|-
  +
| || 170 || N/A || P170S || missense || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM930068 || 190 || Maple syrup urine disease || Q190K || missense || TRUE || disease
  +
|-
  +
| rs190610188 || 199 || N/A || R199C || missense || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| 6 || 204 || MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA || G204S || missense || TRUE || disease
  +
|-
  +
| || 209 || N/A || L209A || missense || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM097509 || 211 || Maple syrup urine disease || T211M || missense || TRUE || disease
  +
|-
  +
| rs10404506 || 213 || N/A || I213I || synonymous-codon || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM984175 || 213 || Maple syrup urine disease || I213T || missense || TRUE || disease
  +
|-
  +
| rs114716391 || 216 || N/A || A216A || synonymous-codon || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM062450 || 216 || Maple syrup urine disease || A216V || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| 8 || 219 || MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA || C219W || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM062451 || 220 || Maple syrup urine disease || A220V || missense || TRUE || disease
  +
|-
  +
| rs141086188 || 221 || N/A || A221T || missense || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| 5 || 225 || MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA || R225W || missense || TRUE || disease
  +
|-
  +
| rs146932786 || 235 || N/A || F235F || synonymous-codon || FALSE || silent
  +
|-
  +
| || 244 || N/A || G244R || missense || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| 3 || 245 || MAPLE SYRUP URINE DISEASE, INTERMEDIATE, TYPE IA || G245R || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM984176 || 249 || Maple syrup urine disease || G249S || missense || TRUE || disease
  +
|-
  +
| rs199599175 || 252 || N/A || A252T || missense || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM930069 || 253 || Maple syrup urine disease || A253T || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM005527 || 254 || Maple syrup urine disease || A254D || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM021498 || 258 || Maple syrup urine disease || C258Y || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| rs137852876 || 263 || True || C263W || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM045934 || 264 || Maple syrup urine disease || C264W || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| rs137852873 || 264 || True || R264W || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| 7 || 265 || MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA || T265R || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM984177 || 265 || Maple syrup urine disease || R265W || missense || TRUE || disease
  +
|-
  +
| || 265 || N/A || R265A || missense || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM984178 || 267 || Maple syrup urine disease || N267S || missense || TRUE || disease
  +
|-
  +
| rs201991385 || 272 || N/A || T272T || synonymous-codon || FALSE || silent
  +
|-
  +
| rs61737367 || 279 || N/A || R279R || synonymous-codon || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM062452 || 283 || Maple syrup urine disease || G283D || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM984179 || 285 || Maple syrup urine disease || A285P || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM970163 || 287 || Maple syrup urine disease || R287* || nonsense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| rs137852871 || 289 || True || G289R || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM950135 || 290 || Maple syrup urine disease || G290R || missense || TRUE || disease
  +
|-
  +
| || 296 || N/A || R296C || missense || FALSE || silent
  +
|-
  +
| rs200137189 || 296 || N/A || R296H || missense || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM062446 || 297 || Maple syrup urine disease || R297C || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM076017 || 297 || Maple syrup urine disease || R297H || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM062453 || 300 || Maple syrup urine disease || G300S || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM062449 || 302 || Maple syrup urine disease || D302A || missense || TRUE || disease
  +
|-
  +
| rs139390622 || 306 || N/A || N306N || synonymous-codon || FALSE || silent
  +
|-
  +
| || 309 || N/A || T309R || missense || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM984180 || 310 || Maple syrup urine disease || T310R || missense || TRUE || disease
  +
|-
  +
| rs144372407 || 313 || N/A || R313Q || missense || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM034725 || 314 || Maple syrup urine disease || R314* || nonsense || TRUE || disease
  +
|-
  +
| rs201109190 || 314 || N/A || R314Q || missense || FALSE || silent
  +
|-
  +
| rs284652 || 323 || N/A || F323F || synonymous-codon || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM930070 || 326 || Maple syrup urine disease || I326T || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM062447 || 327 || Maple syrup urine disease || E327K || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM076018 || 328 || Maple syrup urine disease || A328T || missense || TRUE || disease
  +
|-
  +
| || 337 || N/A || S337D || missense || FALSE || silent
  +
|-
  +
| rs146300600 || 343 || N/A || A343V || missense || FALSE || silent
  +
|-
  +
| || 345 || N/A || R345C || missense || FALSE || silent
  +
|-
  +
| rs139556493 || 345 || N/A || S345L || missense || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM062448 || 346 || Maple syrup urine disease || R346H || missense || TRUE || disease
  +
|-
  +
| rs144276456 || 346 || N/A || S346S || synonymous-codon || FALSE || silent
  +
|-
  +
| rs185688419 || 356 || N/A || Q356R || missense || FALSE || silent
  +
|-
  +
| rs61736656 || 359 || N/A || I359V || missense || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM984181 || 363 || Maple syrup urine disease || R363W || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| 4 || 364 || MAPLE SYRUP URINE DISEASE, INTERMEDIATE, TYPE IA. MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA, INCLUDED || F364C || missense || TRUE || disease
  +
|-
  +
| rs190202447 || 382 || N/A || R382R || synonymous-codon || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| 1 || 393 || MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA || Y393N || missense || TRUE || disease
  +
|-
  +
| rs145595627 || 401 || N/A || P401P || synonymous-codon || FALSE || silent
  +
|-
  +
| || 403 || N/A || P403R || missense || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| rs137852872 || 407 || True || F407C || missense || TRUE || disease
  +
|-
  +
| || 408 || N/A || F408C || missense || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| CM950136 || 409 || Maple syrup urine disease || F409C || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM032853 || 412 || Maple syrup urine disease || V412M || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM082499 || 413 || Maple syrup urine disease || Y413H || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM940169 || 413 || Maple syrup urine disease || Y413C || missense || TRUE || disease
  +
|-
  +
| rs34492894 || 419 || N/A || L419L || synonymous-codon || FALSE || silent
  +
|-
  +
| rs141991700 || 422 || N/A || Q422K || missense || FALSE || silent
  +
|- style="background-color: #FFBBBB;"
  +
| rs137852870 || 436 || True || Y436N || missense || TRUE || disease
  +
|- style="background-color: #FFBBBB;"
  +
| CM890022 || 438 || Maple syrup urine disease || Y438N || missense || TRUE || disease
  +
|}
  +
  +
== Discussion ==
  +
  +
* SNPs are very frequent in human genome.
  +
* Many missense mutations also lead to disease, because a mutation is a random event, which in most cases will lead to a loss of function.
  +
* Nonsense mutations seem to be even more severe. All reported nonsense mutations in BCKDHA are disease causing. The only case, where a nonsense mutation could be neutral, is if the mutation is near the end of the protein, which is unlikely for a random SNP.
  +
* There are disease causing mutations widespread almost over the whole length of the protein. So not only mutations at functionally important sites like binding sites or catalytic centres can cause disease, but also mutations that occur somewhere in the protein and might change its whole structure, which also disturbs the function.
  +
* The databases have different focuses:
  +
** OMIM and HGMD list only disease causing SNPs
  +
** SNPdbe adds information about functional effects of non-synonymous SNPs
  +
** dbSNP aims to collect all known SNPs
  +
  +
== References ==
  +
  +
* Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), 2013. [http://omim.org/ OMIM]
  +
* Stenson et al (2003). The Human Gene Mutation Database (HGMD®): 2003 Update. Hum Mutat(2003) 21:577-581. [http://www.hgmd.org/ HGMD]
  +
* Kitts A, Sherry S. The Single Nucleotide Polymorphism Database (dbSNP) of Nucleotide Sequence Variation. 2002 Oct 9 [Updated 2011 Feb 2]. In: McEntyre J, Ostell J, editors. The NCBI Handbook [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2002-. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK21088/
  +
* [http://www.ncbi.nlm.nih.gov/SNP/ dbSNP]
  +
* Schaefer C, Meier A, Rost B, Bromberg Y (2012). SNPdbe: Constructing an nsSNP functional impacts database. Bioinformatics; 28(4):601-602. [http://www.rostlab.org/services/snpdbe/ SNPdbe]
  +
* Cariaso M, Lennon G. SNPedia: a wiki supporting personal genome annotation, interpretation and analysis. Nucleic Acids Research 2011; doi: 10.1093/nar/gkr798. [http://www.snpedia.com/ SNPedia]

Latest revision as of 18:49, 9 August 2013

HGMD

Database facts

Q: What information is given?

A: Only disease causing mutations are included. HGMD lists the following mutation types:

  • missense/nonsense
  • splicing
  • regulatory
  • small deletions
  • small insertions
  • small indels
  • gross deletions
  • gross insertions/duplications
  • complex rearrangements
  • repeat variations

For each mutation entry the following information is given in the public version:

  • accession number
  • codon change
  • amino acid change
  • codon number
  • phenotype
  • reference
  • comments

Q: How recent is the release?

A: Release 2013.1 is the current professional version. Entries are made publicly accessible three years after they are included. Mutations that are taken from publicly available locus-specific mutation databases are immediately added to the public version.

Q: Where does the information come from?

A: The information is extracted from articles that describe genetic diseases. So only published mutations are included.

Mutations of BCKDHA

The following mutations are listed for BCKDHA (20 June 2013):

mutation type number of mutations
missense/nonsense 40
splicing 2
small deletions 4
small insertions 1
small indels 1
gross deletions 2
complex rearrangements 1


All reported mutations are associated with MSUD. Among the 40 mutations of category "missense/nonsense", there are 37 missense mutations listet and 3 nonsense mutations.

Definition of the mutation types:

  • missense: single base substitution that leads to amino acid change
  • nonsense: single base substitution that leads to a stop codon
  • splicing: mutation that affects a splicing side
  • small deletion: deletion of few base pairs
  • small insertion: insertion of few base pairs
  • small indel: insertion / deletion of few base pairs
  • gross deletion: deletion of many base pairs
  • complex rearrangement: insertion / deletion of many base pairs

dbSNP

Histogram of different types of SNPs reported in dbSNP.

Database facts

Q: What information is given?

A: Short variations in nucleotide sequence from many different organisms. It contains following information:

  • mutations of different categories:
    • single nucleotide variations
    • indels
    • short tandem repeats
    • microsatellites
  • additional information for rare variations
    • disease relationship
    • genotype information
    • allele origin
    • somatic or germline events

Q: How recent is the release?

A: Current version of dbSNP is build 137. dbSNP web query, ftp data and Entrez Indexing were released on Jun 26, 2012. New release of BLAST database is not yet done. The newest release of BLAST database was released on Nov 14, 2011 from build 135.

Q: Where does the information come from?

A: dbSNP is created by the cooperation of the National Human Genome Research Institute and the National Center for Biotechnology Information. It is integrated with the NCBI Genomic data. There are two sorts of content in dbSNP: submitted and computed data. During a build cycle, submitted SNPs (identified by ss#) which map to the same genomic position, are clustered to a non-redundant set of reference SNPs (refSNPs), that get a unique rs# identifier.

Mutations of BCKDHA

Totally 292 SNPs in coding region of BCKDHA were found in dbSNP. 4 mutations are nonsense (stop-gained) which introduce stop condon in the coding region. 152 mutations are missense among which 28 mutations can cause disease. 136 mutations are synonymous codons.

SNPdbe

Database facts

Q: What information is given?

A: Experimentally annotated effects of non-synonymous SNPs (nsSNP). Computationally annotated structural and functional effects of nsSNP. Association between nsSNP and diseases.

Q: How recent is the release?

A: The most recent update took place on Mar 05, 2012.

Q: Where does the information come from?

A: Experimentally annotated nsSNP from dbSNP; Variants from UniProt and PMD; Genomic data from 1000 Genome collection; predicted impacts on protein structure and function are computed with SNAP and SIFT.

Mutations of BCKDHA

102 SNPs were reported in SNPdbe for BCKDHA. Among them 8 SNPs were reported to have association to MSUD.

OMIM

Database facts

Q: What information is given?

A: In the allelic variants section of a gene entry, mutations (e. g. substitions or deletions) are given and the phenotype that they are causing. Only selected mutations are listed (see OMIM FAQ), most of which are disease associated.

Q: How recent is the release?

A: OMIM is updated daily. The entry for BCKDHA was last updated 05/23/2012.

Q: Where does the information come from?

A: The information comes from published articles. For each mutation the reference article is given in the text of the allelic variants section.

Mutations of BCKDHA

For BCKDHA, there are 7 missense mutations listed and 2 deletions, where one is a 1-bp (base pair) deletion and the other 8-bp (last update of entry: 05/23/2012). All these mutations are associated with MSUD type IA (classic or intermediate form).

SNPedia

Database facts

Q: What information is given?

A: The wiki style project 'SNPedia' is open to the internet community. It contains information about effects of SNPs. Annotations from wide range of internet resources such as the dbSNP project, Ensembl or even google search are included into SNPedia. It tries to gather all SNP related information to one web site.

Q: How recent is the release?

A: Due to contribution of its user community, new updates could occur at any time point. But still it depends on the release of other SNP related resources.

Q: Where does the information come from?

A: Many different public available databases, resources about SNPs, publications about genomic studies.

Mutations of BCKDHA

Due the fact that SNPedia is not a database-like data source. Statistics over reported SNPs for BCKDHA is hard to obtain.

Mutation map

102 mutations were selected from different databases. Disease causing mutations are marked in red, mutations that do not cause disease are marked in blue.

Mutation-map.png

Following table contains the SNPs that we have chosen from different databases:

Accession.Number Codon.number Pathogenic Mutation Type pathogenic all
17 N/A L17F missense FALSE silent
29 N/A G29E missense FALSE silent
rs11549936 38 N/A P38H missense FALSE silent
rs80014754 38 N/A P38P synonymous-codon FALSE silent
rs150177278 41 N/A Q41R missense FALSE silent
59 N/A A59V missense FALSE silent
rs149251798 61 N/A I61M missense FALSE silent
CM093772 69 Maple syrup urine disease Q69* nonsense TRUE disease
rs138025447 70 N/A N70N synonymous-codon FALSE silent
rs11549938 81 N/A M81L missense FALSE silent
rs148571328 95 N/A H95H synonymous-codon FALSE silent
rs11549937 96 N/A L96L synonymous-codon FALSE silent
CM005526 109 Maple syrup urine disease M109T missense TRUE disease
rs150700696 111 N/A L111L synonymous-codon FALSE silent
CM021496 125 Maple syrup urine disease Q125E missense TRUE disease
rs139678295 126 N/A R126W missense FALSE silent
rs201638798 133 N/A N133N synonymous-codon FALSE silent
rs146804716 140 N/A H140H synonymous-codon FALSE silent
rs200947033 145 N/A A145A synonymous-codon FALSE silent
CM021497 151 Maple syrup urine disease T151M missense TRUE disease
CM082498 152 Maple syrup urine disease D152N missense TRUE disease
CM930067 159 Maple syrup urine disease R159W missense TRUE disease
CM984173 166 Maple syrup urine disease Y166N missense TRUE disease
CM984174 167 Maple syrup urine disease R167Q missense TRUE disease
170 N/A P170S missense FALSE silent
CM930068 190 Maple syrup urine disease Q190K missense TRUE disease
rs190610188 199 N/A R199C missense FALSE silent
6 204 MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA G204S missense TRUE disease
209 N/A L209A missense FALSE silent
CM097509 211 Maple syrup urine disease T211M missense TRUE disease
rs10404506 213 N/A I213I synonymous-codon FALSE silent
CM984175 213 Maple syrup urine disease I213T missense TRUE disease
rs114716391 216 N/A A216A synonymous-codon FALSE silent
CM062450 216 Maple syrup urine disease A216V missense TRUE disease
8 219 MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA C219W missense TRUE disease
CM062451 220 Maple syrup urine disease A220V missense TRUE disease
rs141086188 221 N/A A221T missense FALSE silent
5 225 MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA R225W missense TRUE disease
rs146932786 235 N/A F235F synonymous-codon FALSE silent
244 N/A G244R missense FALSE silent
3 245 MAPLE SYRUP URINE DISEASE, INTERMEDIATE, TYPE IA G245R missense TRUE disease
CM984176 249 Maple syrup urine disease G249S missense TRUE disease
rs199599175 252 N/A A252T missense FALSE silent
CM930069 253 Maple syrup urine disease A253T missense TRUE disease
CM005527 254 Maple syrup urine disease A254D missense TRUE disease
CM021498 258 Maple syrup urine disease C258Y missense TRUE disease
rs137852876 263 True C263W missense TRUE disease
CM045934 264 Maple syrup urine disease C264W missense TRUE disease
rs137852873 264 True R264W missense TRUE disease
7 265 MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA T265R missense TRUE disease
CM984177 265 Maple syrup urine disease R265W missense TRUE disease
265 N/A R265A missense FALSE silent
CM984178 267 Maple syrup urine disease N267S missense TRUE disease
rs201991385 272 N/A T272T synonymous-codon FALSE silent
rs61737367 279 N/A R279R synonymous-codon FALSE silent
CM062452 283 Maple syrup urine disease G283D missense TRUE disease
CM984179 285 Maple syrup urine disease A285P missense TRUE disease
CM970163 287 Maple syrup urine disease R287* nonsense TRUE disease
rs137852871 289 True G289R missense TRUE disease
CM950135 290 Maple syrup urine disease G290R missense TRUE disease
296 N/A R296C missense FALSE silent
rs200137189 296 N/A R296H missense FALSE silent
CM062446 297 Maple syrup urine disease R297C missense TRUE disease
CM076017 297 Maple syrup urine disease R297H missense TRUE disease
CM062453 300 Maple syrup urine disease G300S missense TRUE disease
CM062449 302 Maple syrup urine disease D302A missense TRUE disease
rs139390622 306 N/A N306N synonymous-codon FALSE silent
309 N/A T309R missense FALSE silent
CM984180 310 Maple syrup urine disease T310R missense TRUE disease
rs144372407 313 N/A R313Q missense FALSE silent
CM034725 314 Maple syrup urine disease R314* nonsense TRUE disease
rs201109190 314 N/A R314Q missense FALSE silent
rs284652 323 N/A F323F synonymous-codon FALSE silent
CM930070 326 Maple syrup urine disease I326T missense TRUE disease
CM062447 327 Maple syrup urine disease E327K missense TRUE disease
CM076018 328 Maple syrup urine disease A328T missense TRUE disease
337 N/A S337D missense FALSE silent
rs146300600 343 N/A A343V missense FALSE silent
345 N/A R345C missense FALSE silent
rs139556493 345 N/A S345L missense FALSE silent
CM062448 346 Maple syrup urine disease R346H missense TRUE disease
rs144276456 346 N/A S346S synonymous-codon FALSE silent
rs185688419 356 N/A Q356R missense FALSE silent
rs61736656 359 N/A I359V missense FALSE silent
CM984181 363 Maple syrup urine disease R363W missense TRUE disease
4 364 MAPLE SYRUP URINE DISEASE, INTERMEDIATE, TYPE IA. MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA, INCLUDED F364C missense TRUE disease
rs190202447 382 N/A R382R synonymous-codon FALSE silent
1 393 MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA Y393N missense TRUE disease
rs145595627 401 N/A P401P synonymous-codon FALSE silent
403 N/A P403R missense FALSE silent
rs137852872 407 True F407C missense TRUE disease
408 N/A F408C missense FALSE silent
CM950136 409 Maple syrup urine disease F409C missense TRUE disease
CM032853 412 Maple syrup urine disease V412M missense TRUE disease
CM082499 413 Maple syrup urine disease Y413H missense TRUE disease
CM940169 413 Maple syrup urine disease Y413C missense TRUE disease
rs34492894 419 N/A L419L synonymous-codon FALSE silent
rs141991700 422 N/A Q422K missense FALSE silent
rs137852870 436 True Y436N missense TRUE disease
CM890022 438 Maple syrup urine disease Y438N missense TRUE disease

Discussion

  • SNPs are very frequent in human genome.
  • Many missense mutations also lead to disease, because a mutation is a random event, which in most cases will lead to a loss of function.
  • Nonsense mutations seem to be even more severe. All reported nonsense mutations in BCKDHA are disease causing. The only case, where a nonsense mutation could be neutral, is if the mutation is near the end of the protein, which is unlikely for a random SNP.
  • There are disease causing mutations widespread almost over the whole length of the protein. So not only mutations at functionally important sites like binding sites or catalytic centres can cause disease, but also mutations that occur somewhere in the protein and might change its whole structure, which also disturbs the function.
  • The databases have different focuses:
    • OMIM and HGMD list only disease causing SNPs
    • SNPdbe adds information about functional effects of non-synonymous SNPs
    • dbSNP aims to collect all known SNPs

References

  • Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), 2013. OMIM
  • Stenson et al (2003). The Human Gene Mutation Database (HGMD®): 2003 Update. Hum Mutat(2003) 21:577-581. HGMD
  • Kitts A, Sherry S. The Single Nucleotide Polymorphism Database (dbSNP) of Nucleotide Sequence Variation. 2002 Oct 9 [Updated 2011 Feb 2]. In: McEntyre J, Ostell J, editors. The NCBI Handbook [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2002-. Chapter 5. Available from: http://www.ncbi.nlm.nih.gov/books/NBK21088/
  • dbSNP
  • Schaefer C, Meier A, Rost B, Bromberg Y (2012). SNPdbe: Constructing an nsSNP functional impacts database. Bioinformatics; 28(4):601-602. SNPdbe
  • Cariaso M, Lennon G. SNPedia: a wiki supporting personal genome annotation, interpretation and analysis. Nucleic Acids Research 2011; doi: 10.1093/nar/gkr798. SNPedia
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