chr4-6301634-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000226760.5(WFS1):c.1839G>A(p.Trp613Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000103 in 1,461,754 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
WFS1
ENST00000226760.5 stop_gained
ENST00000226760.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 5.87
Genes affected
WFS1 (HGNC:12762): (wolframin ER transmembrane glycoprotein) This gene encodes a transmembrane protein, which is located primarily in the endoplasmic reticulum and ubiquitously expressed with highest levels in brain, pancreas, heart, and insulinoma beta-cell lines. Mutations in this gene are associated with Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), an autosomal recessive disorder. The disease affects the brain and central nervous system. Mutations in this gene can also cause autosomal dominant deafness 6 (DFNA6), also known as DFNA14 or DFNA38. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 216 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-6301634-G-A is Pathogenic according to our data. Variant chr4-6301634-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 349320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6301634-G-A is described in Lovd as [Pathogenic]. Variant chr4-6301634-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.1839G>A | p.Trp613Ter | stop_gained | 8/8 | ENST00000226760.5 | NP_005996.2 | |
WFS1 | NM_001145853.1 | c.1839G>A | p.Trp613Ter | stop_gained | 8/8 | NP_001139325.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WFS1 | ENST00000226760.5 | c.1839G>A | p.Trp613Ter | stop_gained | 8/8 | 1 | NM_006005.3 | ENSP00000226760 | P2 | |
ENST00000661896.1 | n.1337+2281C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
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34
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251334Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135846
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461754Hom.: 0 Cov.: 98 AF XY: 0.00000688 AC XY: 5AN XY: 727186
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GnomAD4 genome Cov.: 34
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2022 | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 278 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 33538814, 28559085, 12955714, 26025012, 24890733, 23981289) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 17, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 349320). This premature translational stop signal has been observed in individuals with Wolfram syndrome (PMID: 12955714, 23981289, 28559085). This variant is present in population databases (rs143064649, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Trp613*) in the WFS1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 278 amino acid(s) of the WFS1 protein. - |
WFS1-Related Spectrum Disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 20, 2016 | The WFS1 c.1839G>A (p.Trp613Ter) stop-gained variant has been reported in four studies in which it is found in a compound heterozygous state with a second variant in four individuals with Wolfram syndrome (Cryns et al. 2003; Marshall et al. 2013; Chaussenot et al. 2015; Bischoff et al. 2015). Of note, five additional affected individuals were compound heterozygous for a different nucleotide change, c.1838G>A, that results in the same stop-gained variant at codon 613 (p.Trp613Ter). The p.Trp613Ter variant was absent from a total of 100 controls and is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project, but this is based on only one allele in a region of good sequence coverage so it is presumed to be rare. Based on the potential impact of stop-gained variants and the evidence from the literature, the p.Trp613Ter variant is classified as pathogenic for WFS1-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 31, 2022 | - - |
Diabetes mellitus Pathogenic:1
Pathogenic, no assertion criteria provided | research | Constantin Polychronakos Laboratory, The Research Institute of the McGill University Health Centre | - | PVS1 PS1 PM1 PM2 PP3 PP4 - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at