chr4-6295120-C-G
Variant summary
Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_006005.3(WFS1):c.792C>G(p.Phe264Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F264S) has been classified as Uncertain significance.
Frequency
Consequence
NM_006005.3 missense
Scores
Clinical Significance
Conservation
Publications
- Wolfram-like syndromeInheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
- Wolfram syndromeInheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
- autosomal dominant nonsyndromic hearing loss 6Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- cataract 41Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- Wolfram syndrome 1Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- autosomal dominant nonsyndromic hearing lossInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- early-onset nuclear cataractInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- type 2 diabetes mellitusInheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Likely_benign. The variant received -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.792C>G | p.Phe264Leu | missense_variant | Exon 7 of 8 | ENST00000226760.5 | NP_005996.2 | |
WFS1 | NM_001145853.1 | c.792C>G | p.Phe264Leu | missense_variant | Exon 7 of 8 | NP_001139325.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152202Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000159 AC: 4AN: 251138 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461046Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726824 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000853 AC: 13AN: 152320Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6AN XY: 74478 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:2
This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 264 of the WFS1 protein (p.Phe264Leu). This variant is present in population databases (rs373669861, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 504707). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt WFS1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
BP4, PM2 -
not specified Uncertain:1Benign:1
p.Phe264Leu in exon 7 of WFS1: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, 9 different species including 3 mammals (Crab-eating macaque, david's myotis (bat), and oppossum) have a Leucine (Leu) at this position despite high nearby amino acid conservation. In addition, computational prediction tools do not sugg est a high likelihood of impact to the protein It has been identified in 2/10328 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs373669861). -
Variant summary: WFS1 c.792C>G (p.Phe264Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251138 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.792C>G in individuals affected with Wolfram Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 504707). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1 Uncertain:1
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WFS1-related disorder Uncertain:1
The WFS1 c.792C>G variant is predicted to result in the amino acid substitution p.Phe264Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6296847-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Wolfram syndrome 1 Benign:1
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 rs373669861 in Wolfram's syndrome yet. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at