chr4-6301764-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_006005.3(WFS1):āc.1969A>Gā(p.Met657Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000737 in 1,613,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain risk allele (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M657I) has been classified as Uncertain significance.
Frequency
Consequence
NM_006005.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.1969A>G | p.Met657Val | missense_variant | 8/8 | ENST00000226760.5 | |
WFS1 | NM_001145853.1 | c.1969A>G | p.Met657Val | missense_variant | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WFS1 | ENST00000226760.5 | c.1969A>G | p.Met657Val | missense_variant | 8/8 | 1 | NM_006005.3 | P2 | |
ENST00000661896.1 | n.1337+2151T>C | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152214Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251082Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135744
GnomAD4 exome AF: 0.0000753 AC: 110AN: 1461406Hom.: 0 Cov.: 98 AF XY: 0.0000605 AC XY: 44AN XY: 727028
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152214Hom.: 0 Cov.: 34 AF XY: 0.0000672 AC XY: 5AN XY: 74360
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 30, 2016 | The p.Met657Val variant in WFS1 has been previously reported by our laboratory i n the heterozygous state in one individual with hearing loss, but has been ident ified in 4/66648 of European chromosomes by the Exome Aggregation Consortium (Ex AC, http://exac.broadinstitute.org; dbSNP rs71532861). This frequency is not hig h enough to rule out a pathogenic role. Computational prediction tools and conse rvation analysis do not provide strong support for or against an impact to the p rotein. In summary, the clinical significance of the p.Met657Val variant is unce rtain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 23, 2019 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 657 of the WFS1 protein (p.Met657Val). This variant is present in population databases (rs71532861, gnomAD 0.02%). This missense change has been observed in individual(s) with spinocerebellar ataxia (PMID: 34445196). ClinVar contains an entry for this variant (Variation ID: 215365). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt WFS1 protein function with a negative predictive value of 95%. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 20, 2018 | The M657V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The M657V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The M657V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
WFS1-Related Spectrum Disorders Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
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 | Feb 15, 2022 | - - |
Spastic ataxia Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris | Jan 04, 2021 | - - |
Autosomal dominant nonsyndromic hearing loss 6 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Wolfram syndrome 1 Other:1
Uncertain risk allele, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy.However no sufficient evidence is found to ascertain the role of this particular variant rs71532861 in Wolfram's syndrome yet. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at