rs537052067
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_006005.3(WFS1):c.883G>A(p.Ala295Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000855 in 1,613,850 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 significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A295G) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.883G>A | p.Ala295Thr | missense_variant | 8/8 | ENST00000226760.5 | |
WFS1 | NM_001145853.1 | c.883G>A | p.Ala295Thr | missense_variant | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WFS1 | ENST00000226760.5 | c.883G>A | p.Ala295Thr | missense_variant | 8/8 | 1 | NM_006005.3 | P2 | |
ENST00000661896.1 | n.1337+3237C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152044Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251210Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135808
GnomAD4 exome AF: 0.0000930 AC: 136AN: 1461806Hom.: 0 Cov.: 31 AF XY: 0.000100 AC XY: 73AN XY: 727214
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152044Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74252
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 295 of the WFS1 protein (p.Ala295Thr). This variant is present in population databases (rs537052067, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 166580). 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 | Feb 28, 2024 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 09, 2017 | Variant classified as Uncertain Significance - Favor Benign. The p.Ala295Thr var iant in WFS1 has been previously identified by our laboratory in one Saudi indiv idual with an alternate genetic etiology for the hearing loss. There is limited control information for the WFS1 gene on the Saudi population; therefore, we can not rule out that this variant is part of the spectrum of benign variation in th is population. This variant has been identified in 1/66652 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs537052067). Although this variant has been seen in the general population, it s frequency is not high enough to rule out a pathogenic role. Alanine (Ala) at p osition 295 is not conserved in mammals or in evolutionarily distant species, wi th 1 mammal (Aardvark) having a threonine (Thr) at this position. Additional com putational prediction tools suggest that this variant may not impact the protein , though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Ala295Thr variant is uncertai n, available data suggest that it is more likely to be benign. - |
Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C4551693:Wolfram syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Aug 14, 2021 | The inherited missense variant c.883G>A, p.Ala295Thr identified in the WFS1 gene has not been reported in individuals with WFS1-related disorders. This variant has two heterozygous (0.001%) in gnomAD v3.1.1, suggesting it is not a common benign variant in the populations represented in this database. In silico tools predict conflicting evidence of pathogenicity. Based on the available evidence, the c.883G>A, p.Ala295Thr variant in the WFS1 gene is classified as a variant of uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 25, 2023 | The c.883G>A (p.A295T) alteration is located in exon 8 (coding exon 7) of the WFS1 gene. This alteration results from a G to A substitution at nucleotide position 883, causing the alanine (A) at amino acid position 295 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Wolfram syndrome 1 Uncertain:1
Uncertain significance, 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 rs537052067 in Wolfram's syndrome yet. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at