4-6301641-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_006005.3(WFS1):c.1846G>T(p.Ala616Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_006005.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.1846G>T | p.Ala616Ser | missense_variant | Exon 8 of 8 | ENST00000226760.5 | NP_005996.2 | |
WFS1 | NM_001145853.1 | c.1846G>T | p.Ala616Ser | missense_variant | Exon 8 of 8 | NP_001139325.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152240Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251294Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135826
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461766Hom.: 0 Cov.: 98 AF XY: 0.0000220 AC XY: 16AN XY: 727198
GnomAD4 genome AF: 0.00000656 AC: 1AN: 152358Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74496
ClinVar
Submissions by phenotype
not provided Uncertain:2
Reported in an individual with moderate sensorineural hearing loss, however, has also been identified in 0.3% of Japanese controls (PMID: 29529044); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37277527, 29529044, 36225977, 27018795, 16408729) -
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 616 of the WFS1 protein (p.Ala616Ser). This variant is present in population databases (rs553336498, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features WFS1-related conditions (PMID: 16408729, 37277527). ClinVar contains an entry for this variant (Variation ID: 225514). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt WFS1 protein function with a negative predictive value of 80%. 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. -
Autosomal dominant nonsyndromic hearing loss 6 Uncertain:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at