rs71539657
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_006005.3(WFS1):c.1760G>A(p.Arg587Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_006005.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.1760G>A | p.Arg587Gln | missense_variant | Exon 8 of 8 | ENST00000226760.5 | NP_005996.2 | |
WFS1 | NM_001145853.1 | c.1760G>A | p.Arg587Gln | missense_variant | Exon 8 of 8 | NP_001139325.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000269 AC: 41AN: 152204Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.000553 AC: 139AN: 251378Hom.: 0 AF XY: 0.000508 AC XY: 69AN XY: 135896
GnomAD4 exome AF: 0.000285 AC: 417AN: 1461754Hom.: 0 Cov.: 99 AF XY: 0.000290 AC XY: 211AN XY: 727188
GnomAD4 genome AF: 0.000269 AC: 41AN: 152322Hom.: 0 Cov.: 34 AF XY: 0.000309 AC XY: 23AN XY: 74480
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2025 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 28, 2024 | The WFS1 c.1760G>A; p.Arg587Gln variant (rs71539657) is reported in the literature in a homozygous individual with vision loss and type 1 diabetes (Li 2018). This variant is reported in ClinVar (Variation ID: 215361). This variant is found in the general population with an overall allele frequency of 0.05% (144/282,766 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is neutral (REVEL: 0.119). While the high population frequency suggests that this is likely a benign variant, given the limited clinical data and lack of functional data, the significance of this variant is uncertain at this time. References: Li M et al. A novel mutation of WFS1 gene in a Chinese patient with Wolfram syndrome: a case report. BMC Pediatr. 2018 Mar 17;18(1):116. PMID: 29549887. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 29, 2018 | - - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2016 | The R587Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project reports R587Q was observed in 4/8,600 alleles from individuals of European background. The R587Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 02, 2017 | p.Arg587Gln in exon 8 of WFS1: This variant is not expected to have clinical sig nificance because of its frequency in the general population and the lack of con servation of the amino acid. It has been identified in 0.4% (37/10152) of Ashke nazi Jewish chromosomes Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNP rs71539657). The arginine (Arg) at position 587 is not cons erved across species with 1 mammal (bushbaby) and 10 fish species having a gluta mine (Gln). Additional computational prediction tools do not suggest an impact t o the protein. - |
WFS1-Related Spectrum Disorders Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
WFS1-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 05, 2024 | The WFS1 c.1760G>A variant is predicted to result in the amino acid substitution p.Arg587Gln. This variant was reported in the homozygous state in an individual with Wolfram syndrome (Li et al. 2018. PubMed ID: 29549887). This variant is reported in 0.36% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Type 2 diabetes mellitus;C4551693:Wolfram syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 17, 2022 | - - |
Optic atrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2018 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 31, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Monogenic diabetes Benign:1
Likely benign, criteria provided, single submitter | research | Personalized Diabetes Medicine Program, University of Maryland School of Medicine | Oct 07, 2016 | ACMG Criteria: BS2 (type2diabetesgenetics.org), BP4 - |
Autosomal dominant nonsyndromic hearing loss 6 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at