rs1362648752
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006005.3(WFS1):c.409_424dupGGCCGTCGCGAGGCTG(p.Val142fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,589,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000037 ( 0 hom. )
Consequence
WFS1
NM_006005.3 frameshift
NM_006005.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.125
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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-6289078-A-AGGGCCGTCGCGAGGCT is Pathogenic according to our data. Variant chr4-6289078-A-AGGGCCGTCGCGAGGCT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.409_424dupGGCCGTCGCGAGGCTG | p.Val142fs | frameshift_variant | 4/8 | ENST00000226760.5 | NP_005996.2 | |
WFS1 | NM_001145853.1 | c.409_424dupGGCCGTCGCGAGGCTG | p.Val142fs | frameshift_variant | 4/8 | NP_001139325.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152206Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000439 AC: 9AN: 205180Hom.: 0 AF XY: 0.0000543 AC XY: 6AN XY: 110578
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GnomAD4 exome AF: 0.0000369 AC: 53AN: 1436812Hom.: 0 Cov.: 32 AF XY: 0.0000407 AC XY: 29AN XY: 712300
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74348
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Wolfram syndrome 1 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Breda Genetics srl | Apr 30, 2021 | The variant c.409_424dup (p.Val142Glyfs*110) in the WFS1 gene is reported as pathogenic for Wolfram syndrome 1 and WFS1-related spectrum disorders in ClinVar (Variation ID: 4519), and as pathogenic in the Global Variome shared LOVD database v.3.0. It creates a shift in the reading frame, which is predicted to result in a premature stop codon 110 amino acids downstream and in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is reported with an estimated allele frequency of 0.0000439 in gnomAD exomes, with no homozygous individuals reported. According to the systematic review conducted by De Heredia et al. (2013) about disease-causing mutations in 412 patients with Wolfram syndrome, the c.409_424dup (p.Val142Glyfs*110) is present in about 6.53% of cases (PMID:23429432). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Oct 25, 2021 | PVS1, PM2, PM3 - |
Likely pathogenic, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs1362648752 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Identified in 6.53% of individuals with Wolfram syndrome (de Heredia et al., 2013); This variant is associated with the following publications: (PMID: 17568405, 20738327, 34758253, 15605410, 26875006, 32179840, 32141364, 21602428, 12955714, 27395765, 11161832, 15151504, 21446023, 22238590, 15277431, 33841295, 23429432) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2022 | This sequence change creates a premature translational stop signal (p.Val142Glyfs*110) in the WFS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WFS1 are known to be pathogenic (PMID: 12955714). This variant is present in population databases (rs767046229, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive Wolfram syndrome (PMID: 1161832, 26875006, 32141364). This variant is also known as 425ins16. ClinVar contains an entry for this variant (Variation ID: 4519). For these reasons, this variant has been classified as Pathogenic. - |
Type 2 diabetes mellitus Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
WFS1-Related Spectrum Disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 11, 2019 | Across a selection of available literature, the WFS1 c.409_424dupGGCCGTCGCGAGGCTG (p.Val142GlyfsTer110) variant has been identified in in seven individuals with Wolfram syndrome, including in a homozygous state in four individuals from three families and in a compound heterozygous state in three unrelated individuals (Domenech et al. 2004; Chaussenot et al. 2011; Rohayem et al. 2011). A systematic review of disease-causing variants associated with Wolfram syndrome indicated that the p.Val142GlyfsTer110 variant is present in 6.53% of patients and is a common cause of Wolfram syndrome in the Spanish population (de Heredia et al. 2013; Domenech et al. 2004). The variant was absent from 98 control chromosomes and is reported at a frequency of 0.000103 in the Latino population of the Genome Aggregation Database. Based on the collective evidence, the p.Val142GlyfsTer110 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. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2023 | - - |
Wolfram syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 10, 2017 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at