4-6302398-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_006005.3(WFS1):c.2603G>A(p.Arg868His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000769 in 1,613,028 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R868C) has been classified as Uncertain significance.
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.2603G>A | p.Arg868His | missense_variant | 8/8 | ENST00000226760.5 | |
WFS1 | NM_001145853.1 | c.2603G>A | p.Arg868His | missense_variant | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WFS1 | ENST00000226760.5 | c.2603G>A | p.Arg868His | missense_variant | 8/8 | 1 | NM_006005.3 | P2 | |
ENST00000661896.1 | n.1337+1517C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152228Hom.: 0 Cov.: 35
GnomAD3 exomes AF: 0.0000920 AC: 23AN: 250092Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135608
GnomAD4 exome AF: 0.0000760 AC: 111AN: 1460800Hom.: 0 Cov.: 87 AF XY: 0.0000853 AC XY: 62AN XY: 726738
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152228Hom.: 0 Cov.: 35 AF XY: 0.000108 AC XY: 8AN XY: 74370
ClinVar
Submissions by phenotype
not provided Uncertain:6
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | WFS1: PM5:Supporting, PS4:Supporting - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 14, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 868 of the WFS1 protein (p.Arg868His). This variant is present in population databases (rs56393026, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of WFS1-related conditions (PMID: 26969326, 32883240, 36597107, 36729443). ClinVar contains an entry for this variant (Variation ID: 215403). 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. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 11, 2022 | Reported in a patient with non-syndromic hearing loss in the presence of a second WFS1 variant, although it is unknown if the second WFS1 variant is on the opposite allele (in trans) (Sloan-Heggen et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 26969326, Turkyilmaz2021[article]) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 22, 2017 | - - |
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). 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 17, 2021 | Fan, 2020; Sloan-Heggen, 2016 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 | May 17, 2022 | - - |
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. - |
Autistic behavior Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Mar 22, 2017 | This heterozygous variant in the WFS1 gene (autosomal recessive transmission), inherited from the mother, was present in a male child who also harbours a second variant in the same gene inherited by the father (compound heterozygosity). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at