Gaucher Disease: Task 07 - Research SNPs

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HGMD

HGMD professional was last updated in March 2013. The free public HGMD version provides data from the release of HGMD proffessional in 2008. The database contains the first example of disease causing or disease associated mutations as well as disease-associated/functional polymorphisms. The informations are taken from literature or reported functional studies. Only non-silent mutations in the coding region are considered. Each mutation is stored once in the database. Additional to the infomation shown in the second table below, the information about a mutation includes its associated disease phenotype, chromosomal location, mutation type, gene symbol and the reference of its first literature report. HGMD professional also provides a mutation viewer. The database has access to more than 250 Journals, that are searched by a combination of computerised and manual procedures to find new detected mutations in published articles about germline mutations causing human genetic diseases.


The Glucocerebrosidase has the gene symbol GBA. A research on The Human Gene Mutation Database for GBA leads to the following results:


GBA in HGMD
Mutation Type Number of Mutations Effect of Mutation
Missense/nonsense 256 substitutions of a single base-pair in coding regions, that cause a amino acid or stop/start codon change
Splicing 16 mutations that influence the mRNA splicing
Regulatory 0 different Regulation caused by substitution
Small deletions 26 micro-deletions (< 21 bp)
Small insertions 13 micro-insertions (<21 bp)
Small indels 4 micro-indels (<21 bp)
Gross deletions 3 deletion (>20 bp)
Gross insertions/duplications 1 insertion (>20 bp)
Complex rearrangements 16 rearangement of DNA fragments within the sequence
Repeat variations 0 different number of repeats


GBA is not affected by a regulatory mutations and repeated variations. The mutations on GBA do not only result to Gaucher's disease or influence its phenotype, but may also have an effect on the phenotype of the diseases Parkinson and Alzheimer. HGMD public (2008 update) provides 335 mutations for GBA. On HGMD Professional 2013.1, 380 mutations can be found.


The following table of Missense/nonsense mutations on GBA shows an abridgement of 10 mutations out of all 256 known mutation of the public version of HGMD. The high naumber of mutations show the high liability of GBA on Gaucher causing mutations. Some position specific amino acids have a higher liability to this disease, as more than one mutation on that position can cause a Missense/nonsense mutations, that leads to Gaucher's disease.


Missense/nonsense mutations on GBA
Accession Number Codon change Amino acid change Codon Number
CM081634 cGGC-AGC Gly-Ser 49
CM057078 AGC-ATC Ser-Ile 51
CM044630 gGTG-ATG Val-Met 54
CM960691 gGTG-CTG Val-Leu 54
HM971738 TGT-TCT Cys-Ser 55
CM081630 AGT-AAT Ser-Asn 81
CM950560 ACA-ATA Thr-Ile 82
CM960692 GGG-GAG Gly-Glu 85
CM016030 gCGA-TGA Arg-Term 86
CM950561 aCGG-TGG Arg-Trp 87

dbSNP

The available data in dbSNP (version 138) were released on April 25, 2013. It provides mutation information for the three organisms, Homo Sapiens, Mus Musculus and Bos Taurus. The Database contains single base nucleotide subsitutions as well as short deletion and insertion polymorphisms. On GBA 59 silent mutations were found in dbSNP.

In the Database were 432 Mutation found for homo sapiens on the gene GBA. 59 of them are silent mutations. Some choosen silent mutations are listed in the table below.

Silent mutations on GBA
mRNA Protein refNumber
Allele change Sequence position Residue Codon position
TCT ⇒ TCC 1528, 1754, 1918 Ser 455, 417, 504 rs141710041
CCC ⇒ CCT 646, 872, 1036 Pro 161, 123, 210 rs201615998
TTG ⇒ CTG 245 Leu 28 rs201330214


SNPedia

GBA on SNPedia

5 SNPs were found

SNPdbe

  • The following information (if available) is given on each SAAS (single amino acid substitution):
    • Experimentally derived functional and structural impact
    • Predicted functional effect
    • Associated disease
    • Average heterozygosity
    • Experimental evidence of the nsSNP
    • Evolutionary conservation of wildtype and mutant amino acid
    • Link-outs to external databases
  • Last update: 2012-02-20 (updated to recent Swiss-Prot release (2012-01)).
  • The information comes from various databases (SwissProt, PMD, dbSNP, 1000 Genomes)
  • Currently (2013-06-23) 159142 protein sequences from 2985 organisms are covered in SNPdbe and 1691464 SAASs are referenced, consisting of natural variants, SAASs from mutagenesis experiments and sequencing conflicts
  • Human variants:
    • Overall: 967879 (100%)
    • Observed functional effect: 23121 (2%)
    • Disease associations: 26842 (3%)
    • Observed functional effect and disease: 1629 (0%)

Search for Gaucher disease delivered 174 entries, 147 from them from the human gene GBA and protein P04062. Note: as some of the mutation occur at the same position, there are only 121 distinct mutated positions from the subset of 147.


Experimental evidence Number of mutations Evidence type 120 Not validated 20 by cluster 3 by cluster,freq 2 1000Genome,freq,cluster 1 by freq 1 HapMap,freq,cluster

Conservation score: Likelihood of observing either the wt (wildtype; green bar) or mt (mutant; red bar) at given position in the sequence. The longer the bar the higher the likelihood. The conservation score can be used as a first (simple) estimate of effect (disease causing) or no effect. There are three types of conservation scores: Pssm, Perc and Psic. There is a direct correlation between the length if the bars and Perc scores, however it is difficult to find a threshold for effect. On the contrary, Pssm mt scores below 0 combined with Pssm wt scores above 0 imply very low occurrence of the mutant in comparison of the wild type protein, which implies that the mutation causes a negative effect. We receive like this:

46 no effect
101 effect


OMIM

  • daily updated
  • 21 844 entries (updated 11 June 2013)
  • gene entries → allelic variants (only selected mutations)
  • disease entries
  • relationship between genotype and phenotype (diseases)

OMIM table view of GBA allelic variants

SNP Databases Summary

Mutation map

References

Adrienne Kitts and Stephen Sherry. The Single Nucleotide Polymorphism Database (dbSNP) of Nucleotide Sequence Variation. Chapter 5 in: The NCBI Handbook. Created: October 9, 2002; Last Update: February 2, 2011

Christian Schaefer, Alice Meier, Burkhard Rost, Yana Bromberg (2012). SNPdbe: Constructing an nsSNP functional impacts database. Bioinformatics 28(4):601-602.

OMIM FAQs

genenames.org report about GBA