4-6301997-C-T
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_006005.3(WFS1):c.2202C>T(p.Leu734Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,612,698 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00039 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000092 ( 2 hom. )
Consequence
WFS1
NM_006005.3 synonymous
NM_006005.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.966
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 -17 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
Variant 4-6301997-C-T is Benign according to our data. Variant chr4-6301997-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 45450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6301997-C-T is described in Lovd as [Benign]. Variant chr4-6301997-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.966 with no splicing effect.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.2202C>T | p.Leu734Leu | synonymous_variant | 8/8 | ENST00000226760.5 | NP_005996.2 | |
WFS1 | NM_001145853.1 | c.2202C>T | p.Leu734Leu | synonymous_variant | 8/8 | NP_001139325.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000388 AC: 59AN: 152236Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000191 AC: 47AN: 246248Hom.: 1 AF XY: 0.000216 AC XY: 29AN XY: 134194
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GnomAD4 exome AF: 0.0000918 AC: 134AN: 1460344Hom.: 2 Cov.: 98 AF XY: 0.0000991 AC XY: 72AN XY: 726462
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GnomAD4 genome AF: 0.000394 AC: 60AN: 152354Hom.: 0 Cov.: 34 AF XY: 0.000349 AC XY: 26AN XY: 74504
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:5
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 06, 2025 | - - |
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 | GeneDx | May 05, 2020 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
not specified Benign:3
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 30, 2012 | Leu734Leu in Exon 08 of WFS1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.1% (2/3728) of Afric an American chromosomes from a broad population by the NHLBI Exome Sequencing Pr oject (http://evs.gs.washington.edu/EVS; dbSNP rs140427062). - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 29, 2021 | - - |
Wolfram syndrome 1 Benign:1
Benign, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However no sufficient evidence is found to ascertain the role of this particular variant rs140427062 in Wolfram's syndrome yet. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at