chr4-6291313-A-C
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_006005.3(WFS1):āc.577A>Cā(p.Lys193Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00371 in 1,613,240 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Consequence
NM_006005.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.577A>C | p.Lys193Gln | missense_variant | Exon 5 of 8 | ENST00000226760.5 | NP_005996.2 | |
WFS1 | NM_001145853.1 | c.577A>C | p.Lys193Gln | missense_variant | Exon 5 of 8 | NP_001139325.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00267 AC: 405AN: 151782Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00380 AC: 951AN: 250524Hom.: 5 AF XY: 0.00437 AC XY: 593AN XY: 135570
GnomAD4 exome AF: 0.00382 AC: 5578AN: 1461340Hom.: 28 Cov.: 35 AF XY: 0.00409 AC XY: 2973AN XY: 726938
GnomAD4 genome AF: 0.00265 AC: 403AN: 151900Hom.: 1 Cov.: 32 AF XY: 0.00296 AC XY: 220AN XY: 74212
ClinVar
Submissions by phenotype
not provided Benign:8
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WFS1: BS1, BS2 -
not specified Benign:4
p.Lys193Gln in exon 5 of WFS1: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (30/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs41264699). -
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Autosomal dominant nonsyndromic hearing loss 6 Benign:2
The heterozygous p.Lys193Gln variant in WFS1 has been identified in an individual with sensorineural hearing loss and in the compound heterozygous state in an individual with gait instability, optic atrophy, and cerebellar dysarthria (PMID: 12073007, 25497598), and has been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant sensorineural hearing loss. -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Wolfram syndrome 1 Pathogenic:1
Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs41264699 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. This variant is found to be a potent moderate impact, deleterious variant with a CADD score of 24 and sufficient scientific evidence to support the reported classification. This is found more frequently in Wolfram syndrome cases as per recent evidence as well. -
WFS1-Related Spectrum Disorders Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1 Benign:1
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Monogenic diabetes Benign:1
ACMG criteria: BS1 (1.3% in gnomAD S Asian, 1% gnomAD AJ), BS2 (74 cases and 62 control in T2DM and 5 homozygotes in gnomAD)=benign (REVEL 0.223 + PP3/5 predictors + BP4/4 predictors: conflicting evidence, not using) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at