4-6291379-C-T
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Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong
The NM_006005.3(WFS1):c.631+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,610,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.00075 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )
Consequence
WFS1
NM_006005.3 intron
NM_006005.3 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.267
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 -10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 4-6291379-C-T is Benign according to our data. Variant chr4-6291379-C-T is described in ClinVar as [Benign]. Clinvar id is 227153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6291379-C-T is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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WFS1 | NM_006005.3 | c.631+12C>T | intron_variant | ENST00000226760.5 | |||
WFS1 | NM_001145853.1 | c.631+12C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WFS1 | ENST00000226760.5 | c.631+12C>T | intron_variant | 1 | NM_006005.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.000749 AC: 114AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000225 AC: 55AN: 244136Hom.: 0 AF XY: 0.000143 AC XY: 19AN XY: 132742
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GnomAD4 exome AF: 0.000100 AC: 146AN: 1458694Hom.: 0 Cov.: 35 AF XY: 0.0000868 AC XY: 63AN XY: 725646
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GnomAD4 genome AF: 0.000749 AC: 114AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49AN XY: 74468
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ClinVar
Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 29, 2016 | 631+12C>T in Intron 05 of WFS1: This variant is not expected to have clinical si gnificance because it is not located within the conserved splice consensus seque nce and has been identified in 0.3% (25/9514) of African chromosomes by the Exom e Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs18398045 4). - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 20, 2015 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
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 rs183980454 in Wolfram's syndrome yet. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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