rs376341411
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_006005.3(WFS1):c.1984T>C(p.Ser662Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,406 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. S662S) has been classified as Likely benign.
Frequency
Consequence
NM_006005.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.1984T>C | p.Ser662Pro | missense_variant | 8/8 | ENST00000226760.5 | |
WFS1 | NM_001145853.1 | c.1984T>C | p.Ser662Pro | missense_variant | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WFS1 | ENST00000226760.5 | c.1984T>C | p.Ser662Pro | missense_variant | 8/8 | 1 | NM_006005.3 | P2 | |
ENST00000661896.1 | n.1337+2136A>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152198Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250930Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135652
GnomAD4 exome AF: 0.00000890 AC: 13AN: 1461208Hom.: 0 Cov.: 99 AF XY: 0.00000963 AC XY: 7AN XY: 726950
GnomAD4 genome ? AF: 0.000112 AC: 17AN: 152198Hom.: 0 Cov.: 34 AF XY: 0.0000673 AC XY: 5AN XY: 74342
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 28, 2013 | The Ser662Pro variant in WFS1 has not been reported in individuals with hearing loss, but has been identified in 0.05% (2/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Compu tational analyses (biochemical amino acid properties, conservation, AlignGVGD, P olyPhen2, and SIFT) suggest that the Ser662Pro variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. In s ummary, additional data is needed to determine the clinical significance of this variant. - |
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 | May 04, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 12, 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. 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 expected to disrupt WFS1 protein function. ClinVar contains an entry for this variant (Variation ID: 166600). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. This variant is present in population databases (rs376341411, gnomAD 0.04%). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 662 of the WFS1 protein (p.Ser662Pro). - |
Wolfram syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 25, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at