rs145677667
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_006005.3(WFS1):c.799G>A(p.Asp267Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000412 in 1,613,146 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_006005.3 missense
Scores
Clinical Significance
Conservation
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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.799G>A | p.Asp267Asn | missense_variant | Exon 7 of 8 | ENST00000226760.5 | NP_005996.2 | |
WFS1 | NM_001145853.1 | c.799G>A | p.Asp267Asn | missense_variant | Exon 7 of 8 | NP_001139325.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000296 AC: 45AN: 152218Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000235 AC: 59AN: 251010Hom.: 0 AF XY: 0.000236 AC XY: 32AN XY: 135860
GnomAD4 exome AF: 0.000424 AC: 620AN: 1460928Hom.: 0 Cov.: 31 AF XY: 0.000413 AC XY: 300AN XY: 726766
GnomAD4 genome AF: 0.000296 AC: 45AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21AN XY: 74364
ClinVar
Submissions by phenotype
not provided Uncertain:5Benign:1
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Observed in a patient with Wolfram syndrome who harbored a second variant in the WFS1 gene (PMID: 26969326); Identified in an individual with vision loss; a second variant in WFS1 was not identified (PMID: 32483926); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29529044, 34426522, 33841295, 26969326, 32483926, 34515852) -
PM2_supporting -
not specified Uncertain:1
The Asp267Asn variant in WFS1 has not been reported in individuals with hearing loss, but has been identified in 0.07% (6/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs145677667). Although this variant has been seen in the general population, it s frequency is not high enough to rule out a pathogenic role. Computational ana lyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, an d SIFT) do not provide strong support for or against an impact to the protein. I n summary, additional data is needed to determine the clinical significance of t his 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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at