rs147147660
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_006005.3(WFS1):c.728C>T(p.Ala243Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000402 in 1,613,594 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A243T) has been classified as Uncertain significance.
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.728C>T | p.Ala243Val | missense_variant | 7/8 | ENST00000226760.5 | |
WFS1 | NM_001145853.1 | c.728C>T | p.Ala243Val | missense_variant | 7/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WFS1 | ENST00000226760.5 | c.728C>T | p.Ala243Val | missense_variant | 7/8 | 1 | NM_006005.3 | P2 | |
ENST00000661896.1 | n.1338-2397G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000298 AC: 75AN: 251324Hom.: 0 AF XY: 0.000338 AC XY: 46AN XY: 135904
GnomAD4 exome AF: 0.000429 AC: 627AN: 1461270Hom.: 1 Cov.: 31 AF XY: 0.000433 AC XY: 315AN XY: 726946
GnomAD4 genome AF: 0.000138 AC: 21AN: 152324Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74482
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 07, 2021 | This variant is associated with the following publications: (PMID: 25133958) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 27, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 04, 2018 | Variant classified as Uncertain Significance - Favor Benign. The p.Ala243Val var iant in WFS1 has been previously reported in an 81-year-old European individual with cerebellar ataxia who also harbored the c.1366C>T p.Arg456Cys variant in WF S1 (Fogel 2014). This variant has also been identified in 0.12% (38/30778) of So uth Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computationa l prediction tools and conservation analysis suggest that this variant may not i mpact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is un certain, these data suggest that it is more likely to be benign. ACMG/AMP Criter ia applied: BS1_Supporting, BP4. - |
WFS1-Related Spectrum Disorders Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 26, 2022 | Unlikely to be causative of WFS1-related Wolfram syndrome (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
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 | Oct 31, 2018 | - - |
Monogenic diabetes Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Personalized Diabetes Medicine Program, University of Maryland School of Medicine | May 18, 2018 | ACMG criteria: (PP3 (4 predictors), BP4 (5 predictors), Revel score 0.160; conflicting evidence, not using), variant found in 81-year old F w cerebellar ataxia but no DM noted (PMID: 25133958), no pathogenic variants in this exon in ClinVar= VUS - |
Autosomal dominant nonsyndromic hearing loss 6 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at