rs201557396
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_006005.3(WFS1):c.1556C>T(p.Ala519Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,612,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A519A) has been classified as Likely benign.
Frequency
Consequence
NM_006005.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.1556C>T | p.Ala519Val | missense_variant | 8/8 | ENST00000226760.5 | |
WFS1 | NM_001145853.1 | c.1556C>T | p.Ala519Val | missense_variant | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WFS1 | ENST00000226760.5 | c.1556C>T | p.Ala519Val | missense_variant | 8/8 | 1 | NM_006005.3 | P2 | |
ENST00000661896.1 | n.1337+2564G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152238Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250548Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135550
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1460070Hom.: 0 Cov.: 100 AF XY: 0.00000688 AC XY: 5AN XY: 726428
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152356Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74490
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2021 | Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 22, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 166592). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. This variant is present in population databases (rs201557396, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 519 of the WFS1 protein (p.Ala519Val). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 29, 2014 | The p.Ala519Val variant in WFS1 has not been previously reported in individuals with hearing loss but has been identified in 0.833% (1/120) of Columbian chromos omes by the 1000 Genomes Project (dbSNP rs201557396). Computational prediction t ools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the Ala519Val variant is uncertain. - |
Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 20, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at