Difference between revisions of "Sequence based mutation analysis of GBA"

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(→‎SNP Selection)
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[''Note that the positions of the SNPs listed in HGMD in this table are different from the corresponding codon numbers, indicated in [[Glucocerebrosidase_mapping_snps | Task 5]], as this position is relative to the sequence of GBA including the signal peptide (+ 39 residues).'']
  
[''Note that the positions of the SNPs listed in HGMD in this table are different from the corresponding codon numbers, indicated in [[Glucocerebrosidase_mapping_snps | Task 5]], as this position is relative to the sequence of GBA including the signal peptide (+ 39 residues).'']
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=== Physicochemical Properties and Changes ===
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== Mutation Analysis ==
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=== SNAP ===
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=== SIFT ===
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''' Usage '''
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* Webserver: http://sift.jcvi.org/www/SIFT_seq_submit2.html
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* Input: sequence in fasta format, substitutions of interest (Example for mutation 1: <code>G49S</code>)
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''' Results '''
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At the moment the connection to the server gets aborted all the time. Results will be posted soon.
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=== Polyphen2 ===
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''' Usage '''
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* Webserver: http://genetics.bwh.harvard.edu/pph2/
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* Input: sequence in fasta format, position and substitution of mutation
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''' Results '''
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The results of PolyPhen-2 (HumDiv) are listed in the table below. Three mutations (Numbers 3, 6 and 8) have been predicted to be harmless.
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<br/>
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{| border="1" style="text-align:center; border-spacing:0" align="center" cellpadding="3" cellspacing="3"
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|-
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|| ''' Mutation Nr.''' || '''Prediction '''||''' Score''' || '''Sensitivity''' || '''Specificity '''
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|-
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|| '''1''' || probably damaging || 0.997 || 0.40 || 0.98
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|-
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|| '''2''' || probably damaging || 1.000 || 0.00 || 1.00
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|-
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|| ''' 3 ''' || benign || 0.000 || 1.00 || 0.00
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|-
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|| '''4''' || probably damaging || 1.000 || 0.00 || 1.00
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|-
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|| ''' 5 ''' || probably damaging || 1.000 || 0.00 || 1.00
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|-
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|| ''' 6 ''' || benign || 0.100 || 0.94 || 0.85
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|-
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|| ''' 7 ''' || probably damaging || 1.000 || 0.00 || 1.00
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|-
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|| ''' 8 ''' || benign || 0.001 || 0.99 || 0.15
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|-
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|| ''' 9 ''' || probably damaging || 0.999 || 0.14 || 0.99
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|-
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|| ''' 10 ''' || probably damaging || 0.978 || 0.75 || 0.96
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|}
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== Discussion ==

Revision as of 18:25, 21 June 2011

Subset of SNPs

The ten SNPs shown in the table below and highlighted in Figure 1 were chosen for the analysis in this task. It was tried to include SNPs all over the protein, in order to investigate the influence of mutations in several parts of the protein. The mutated residues forming hydrogenbonds with the active site of glucocerebrosidase are included, as these should result in either a mal- or nonfunctioning protein. It was not easy to find missense mutations only listed in dbSNP, as most of them were listed in HGMD, too.

Figure 1: Selected mutations highlighted on structure of 10GS. The different colors indicate, in which database the mutation is listed: dbSNP (blue), HGMD (red), both (green)
Nr. SNP ID/Accession Number Database Position Amino Acid Change Codon Change Remarks
1 CM081634 HGMD 49 Gly - Ser cGGC-AGC
2 rs74953658, CM050263 dbSNP, HGMD 63 Asp-Asn tGAC-AAC
3 rs1141820 dbSNP 99 His - Arg CAC - CGC suspected, status not validated
4 CM880035 HGMD 159 Arg - Gln CGG-CAG Synonymos Mutation at this position listed in dbSNP
5 rs80205046, CM041347 dbSNP, HGMD 221 Pro - Leu CCC - CTC
6 rs74731340, CM970620 dbSNP, HGMD 310 Ser - Asn AGT - AAT
7 CM993703 HGMD 350 His - Arg CAT - CGT
8 CM960698 HGMD 426 Pro - Leu CCC-CTC
9 rs80020805, CM052245 dbSNP, HGMD 455 Met - Val cATG-GTG
10 rs113825752 dbSNP 509 Leu - Pro CTT - CCT


[Note that the positions of the SNPs listed in HGMD in this table are different from the corresponding codon numbers, indicated in Task 5, as this position is relative to the sequence of GBA including the signal peptide (+ 39 residues).]

Physicochemical Properties and Changes

Mutation Analysis

SNAP

SIFT

Usage

Results

At the moment the connection to the server gets aborted all the time. Results will be posted soon.


Polyphen2

Usage

Results

The results of PolyPhen-2 (HumDiv) are listed in the table below. Three mutations (Numbers 3, 6 and 8) have been predicted to be harmless.


Mutation Nr. Prediction Score Sensitivity Specificity
1 probably damaging 0.997 0.40 0.98
2 probably damaging 1.000 0.00 1.00
3 benign 0.000 1.00 0.00
4 probably damaging 1.000 0.00 1.00
5 probably damaging 1.000 0.00 1.00
6 benign 0.100 0.94 0.85
7 probably damaging 1.000 0.00 1.00
8 benign 0.001 0.99 0.15
9 probably damaging 0.999 0.14 0.99
10 probably damaging 0.978 0.75 0.96

Discussion

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