Task 7 (MSUD)

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 only missense mutations listet and no 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

100 mutations were selected from different databases. Disease causing mutations are marked in red, synonymous mutations are marked in blue.

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

Accession.Number	Codon.number	Pathogenic	Mutation	Type
	29	N/A	G29E	missense
rs11549936	38	N/A	P38H	missense
rs150177278	41	N/A	Q41R	missense
	59	N/A	A59V	missense
	62	N/A	I62M	missense
CM093772	69	Maple syrup urine disease	Q69*	nonsense
	71	N/A	N71S	missense
	82	N/A	M82I	missense
rs148571328	95	N/A	H95H	synonymous-codon
CM005526	109	Maple syrup urine disease	M109T	missense
rs150700696	111	N/A	L111L	synonymous-codon
CM021496	125	Maple syrup urine disease	Q125E	missense
	127	N/A	R127W	missense
rs146804716	140	N/A	H140H	synonymous-codon
rs34442879	150	N/A	T150M	missense
CM021497	151	Maple syrup urine disease	T151M	missense
CM082498	152	Maple syrup urine disease	D152N	missense
CM930067	159	Maple syrup urine disease	R159W	missense
	159	N/A	R159A	missense
	159	maple syrup urine disease type ia (SwissVar)	R159W	missense
CM984173	166	Maple syrup urine disease	Y166N	missense
CM984174	167	Maple syrup urine disease	R167Q	missense
CM930068	190	Maple syrup urine disease	Q190K	missense
	190	maple syrup urine disease type ia (SwissVar)	Q190K	missense
rs190610188	199	N/A	R199C	missense
6	204	MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA	G204S	missense
	209	N/A	L209A	missense
CM097509	211	Maple syrup urine disease	T211M	missense
CM984175	213	Maple syrup urine disease	I213T	missense
rs114716391	215	N/A	A215A	synonymous-codon
CM062450	216	Maple syrup urine disease	A216V	missense
8	219	MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA	C219W	missense
5	220	MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA	R220W	missense
CM062451	220	Maple syrup urine disease	A220V	missense
	222	N/A	A222T	missense
	244	N/A	G244R	missense
3	245	MAPLE SYRUP URINE DISEASE, INTERMEDIATE, TYPE IA	G245R	missense
rs137852874	248	True	G248S	missense
CM984176	249	Maple syrup urine disease	G249S	missense
rs199599175	252	N/A	A252T	missense
CM930069	253	Maple syrup urine disease	A253T	missense
	253	maple syrup urine disease type ia (SwissVar)	A253T	missense
CM005527	254	Maple syrup urine disease	A254D	missense
CM021498	258	Maple syrup urine disease	C258Y	missense
rs137852876	263	True	C263W	missense
CM045934	264	Maple syrup urine disease	C264W	missense
	264	N/A	C264W	missense
rs137852873	264	True	R264W	missense
7	265	MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA	T265R	missense
CM984177	265	Maple syrup urine disease	R265W	missense
	265	N/A	R265W	missense
CM984178	267	Maple syrup urine disease	N267S	missense
rs61737367	279	N/A	R279R	synonymous-codon
CM062452	283	Maple syrup urine disease	G283D	missense
CM984179	285	Maple syrup urine disease	A285P	missense
CM970163	287	Maple syrup urine disease	R287*	nonsense
rs137852871	289	True	G289R	missense
CM950135	290	Maple syrup urine disease	G290R	missense
	290	maple syrup urine disease type ia (SwissVar)	G290R	missense
	296	N/A	R296C	missense
CM062446	297	Maple syrup urine disease	R297C	missense
CM076017	297	Maple syrup urine disease	R297H	missense
CM062453	300	Maple syrup urine disease	G300S	missense
CM062449	302	Maple syrup urine disease	D302A	missense
rs139390622	306	N/A	N306N	synonymous-codon
	309	N/A	T309R	missense
rs137852875	309	True	T309R	missense
CM984180	310	Maple syrup urine disease	T310R	missense
CM034725	314	Maple syrup urine disease	R314*	missense
rs201109190	314	N/A	R314Q	missense
rs284652	323	N/A	F323F	synonymous-codon
CM930070	326	Maple syrup urine disease	I326T	missense
	326	maple syrup urine disease type ia (SwissVar)	I326T	missense
CM062447	327	Maple syrup urine disease	E327K	missense
CM076018	328	Maple syrup urine disease	A328T	missense
rs146300600	343	N/A	A343V	missense
	345	N/A	R345C	missense
CM062448	346	Maple syrup urine disease	R346H	missense
rs144276456	346	N/A	S346S	synonymous-codon
	356	N/A	Q356R	missense
	361	N/A	I361V	missense
CM984181	363	Maple syrup urine disease	R363W	missense
4	364	MAPLE SYRUP URINE DISEASE, INTERMEDIATE, TYPE IA. MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA, INCLUDED	F364C	missense
1	393	MAPLE SYRUP URINE DISEASE, CLASSIC, TYPE IA	Y393N	missense
	398	N/A	E398K	missense
rs145595627	401	N/A	P401P	synonymous-codon
	403	N/A	N403S	missense
rs137852872	407	True	F407C	missense
	408	N/A	F408C	missense
CM950136	409	Maple syrup urine disease	F409C	missense
	409	maple syrup urine disease type ia (SwissVar)	F409C	missense
CM032853	412	Maple syrup urine disease	V412M	missense
CM082499	413	Maple syrup urine disease	Y413H	missense
CM940169	413	Maple syrup urine disease	Y413C	missense
	413	maple syrup urine disease type ia (SwissVar)	Y413C	missense
rs141991700	422	N/A	Q422K	missense
	428	N/A	R428H	missense
rs137852870	436	True	Y436N	missense
CM890022	438	Maple syrup urine disease	Y438N	missense
	438	maple syrup urine disease type ia (SwissVar)	Y438N	missense

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