rs56002719
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1PP3BP4_StrongBP6_Very_StrongBS2
The NM_006005.3(WFS1):c.2327A>T(p.Glu776Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00424 in 1,612,924 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0034 ( 3 hom., cov: 34)
Exomes 𝑓: 0.0043 ( 28 hom. )
Consequence
WFS1
NM_006005.3 missense
NM_006005.3 missense
Scores
9
7
2
Clinical Significance
Conservation
PhyloP100: 8.77
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 Benign. Variant got -13 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 uncertain in NM_006005.3
PP3
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.066612035).
BP6
Variant 4-6302122-A-T is Benign according to our data. Variant chr4-6302122-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 166606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6302122-A-T is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAd4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.2327A>T | p.Glu776Val | missense_variant | 8/8 | ENST00000226760.5 | |
WFS1 | NM_001145853.1 | c.2327A>T | p.Glu776Val | missense_variant | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WFS1 | ENST00000226760.5 | c.2327A>T | p.Glu776Val | missense_variant | 8/8 | 1 | NM_006005.3 | P2 | |
ENST00000661896.1 | n.1337+1793T>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.00337 AC: 513AN: 152216Hom.: 3 Cov.: 34
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GnomAD3 exomes AF: 0.00380 AC: 941AN: 247476Hom.: 2 AF XY: 0.00377 AC XY: 507AN XY: 134604
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GnomAD4 exome AF: 0.00433 AC: 6322AN: 1460590Hom.: 28 Cov.: 98 AF XY: 0.00419 AC XY: 3046AN XY: 726594
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GnomAD4 genome AF: 0.00337 AC: 513AN: 152334Hom.: 3 Cov.: 34 AF XY: 0.00368 AC XY: 274AN XY: 74488
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:8
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 28, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | WFS1: BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 04, 2020 | Identified in patients with Wolfram syndrome who harbored a second missense variant in the WFS1 gene in published literature but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Smith et al., 2004; Astuti et al., 2017); This variant is associated with the following publications: (PMID: 21446023, 20981092, 24909696, 15277431, 28432734, 30245029, 31638168) - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 07, 2012 | Glu776Val in Exon 08 of WFS1: This variant is not expected to have clinical sign ificance because it has been identified in 0.4% (31/7006) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs56002719). - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 21, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 21, 2017 | - - |
WFS1-Related Spectrum Disorders Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
WFS1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 15, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Nonsyndromic genetic hearing loss Benign:1
Benign, criteria provided, single submitter | clinical testing | INGEBI, INGEBI / CONICET | Jul 15, 2021 | Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The filter allele frequency of the c.2327A>T in WFS1 gene is 0,5% for european non-finnish and 1% for european finnish (calculatin with 95%CI) in gnomAD database, exceeding the treshold for dominant HL, meeting BA1. Computational analysis predicted a pathogenic effect of the mutation to the protein, REVEL= 0,98 (PP3). Our internal data demonstrated that the variant seggregated with the affected mother and grandother applying for PP1_Sup. However, there is a report in which the variant did not segregate with the pathology in a family (an unaffected sibling and father carried the mutation) meeting BS4. Taking into account the evidence: BA1, PP3, PP1_Sup and BS4 the vartiant is classified as Benign. - |
Monogenic diabetes Benign:1
Benign, criteria provided, single submitter | research | Personalized Diabetes Medicine Program, University of Maryland School of Medicine | Mar 10, 2017 | ACMG Criteria:PP3 (10 predictors), BS1 (1.15% in ExAC Finnish population, 1 homo in ExAC), BS2 (39 cases and 42 controls in type2diabetesgenetics.org) - |
Autosomal dominant nonsyndromic hearing loss 6 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D
MetaRNN
Benign
T;T
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
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