4-6301941-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_006005.3(WFS1):c.2146G>A(p.Ala716Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,508 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A716A) has been classified as Likely benign.
Frequency
Consequence
NM_006005.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.2146G>A | p.Ala716Thr | missense_variant | 8/8 | ENST00000226760.5 | |
WFS1 | NM_001145853.1 | c.2146G>A | p.Ala716Thr | missense_variant | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WFS1 | ENST00000226760.5 | c.2146G>A | p.Ala716Thr | missense_variant | 8/8 | 1 | NM_006005.3 | P2 | |
ENST00000661896.1 | n.1337+1974C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 exomes AF: 0.00000804 AC: 2AN: 248846Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135078
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460508Hom.: 0 Cov.: 99 AF XY: 0.00000413 AC XY: 3AN XY: 726570
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2023 | For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WFS1 protein function. ClinVar contains an entry for this variant (Variation ID: 4520). This missense change has been observed in individual(s) with autosomal dominant nonsyndromic deafness (PMID: 11709537, 11709538; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs28937893, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 716 of the WFS1 protein (p.Ala716Thr). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 12, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11709537, 11709538, 17492394, 12490066, 12707188, 28432734, 29529044, 29277467, 36208030, 36225977, 34599366, 36098976) - |
Autosomal dominant nonsyndromic hearing loss 6 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2007 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 16, 2016 | The p.Ala716Thr variant in WFS1 has been reported in six families with low frequ ency sensorineural hearing loss and was shown to segregate in >30 affected famil y members (Bespalova 2001, Young 2001, Fukuoka 2007, LMM Data). All individuals heterozygous for the p.Ala716Thr variant were reported to have only hearing loss , and one individual homozygous for the variant had clinical features of Wolfram syndrome (Young 2001). This variant has been identified in 1/30736 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinsti tute.org/; dbSNP rs28937893). In summary, this variant meets criteria to be clas sified as pathogenic for autosomal dominant hearing loss; however, its clinical significance for autosomal recessive Wolfram syndrome is uncertain. ACMG/AMP Cri teria applied: PP1_Strong; PM2; PS4_Moderate; PP3. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at