4-6302449-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_006005.3(WFS1):c.2654C>T(p.Pro885Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,612,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P885P) has been classified as Likely benign.
Frequency
Consequence
NM_006005.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.2654C>T | p.Pro885Leu | missense_variant | 8/8 | ENST00000226760.5 | |
WFS1 | NM_001145853.1 | c.2654C>T | p.Pro885Leu | missense_variant | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WFS1 | ENST00000226760.5 | c.2654C>T | p.Pro885Leu | missense_variant | 8/8 | 1 | NM_006005.3 | P2 | |
ENST00000661896.1 | n.1337+1466G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152268Hom.: 0 Cov.: 35
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249382Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135456
GnomAD4 exome AF: 0.0000698 AC: 102AN: 1460690Hom.: 0 Cov.: 87 AF XY: 0.0000716 AC XY: 52AN XY: 726676
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152268Hom.: 0 Cov.: 35 AF XY: 0.0000403 AC XY: 3AN XY: 74394
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | WFS1: PM2, PM3, PP4, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 14, 2022 | This missense change has been observed in individuals with autosomal recessive Wolfram syndrome (PMID: 10521293, 28432734). This variant is present in population databases (rs372855769, gnomAD 0.004%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 885 of the WFS1 protein (p.Pro885Leu). ClinVar contains an entry for this variant (Variation ID: 437297). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects WFS1 function (PMID: 16806192). 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 expected to disrupt WFS1 protein function. - |
Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 18, 2021 | - - |
Wolfram-like syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Feb 14, 2019 | - - |
Wolfram syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Feb 28, 2023 | PS3, PM1, PM2, PM3_Supporting, PP3 - |
Autosomal dominant nonsyndromic hearing loss 6 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has been previously reported as a heterozygous and homozygous change in patients with Wolfram-like Syndrome/ Wolfram Syndrome (PMID: 10521293, 30773290, 28432734). In vitro analysis illustrated that the c.2654C>T (p.Pro885Leu) variant results in reduce protein expression affecting WFS1 function (PMID: 16806192). The c.2654C>T (p.Pro885Leu) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/249382) and thus is presumed to be rare. The c.2654C>T (p.Pro885Leu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.2654C>T (p.Pro885Leu) variant is classified as Pathogenic. - |
Wolfram syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 11, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at