rs121434226
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The ENST00000367021.8(IRF6):c.250C>T(p.Arg84Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R84G) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000367021.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
IRF6 | NM_006147.4 | c.250C>T | p.Arg84Cys | missense_variant | 4/9 | ENST00000367021.8 | NP_006138.1 | |
IRF6 | NM_001206696.2 | c.-36C>T | 5_prime_UTR_variant | 2/7 | NP_001193625.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IRF6 | ENST00000367021.8 | c.250C>T | p.Arg84Cys | missense_variant | 4/9 | 1 | NM_006147.4 | ENSP00000355988 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461674Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727142
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Autosomal dominant popliteal pterygium syndrome Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | Most commonly seen in persons with popliteal pterygium syndrome - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine | May 26, 2023 | - - |
Popliteal pterygium syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2002 | - - |
Van der Woude syndrome;C0265259:Popliteal pterygium syndrome;C1837213:Orofacial cleft 6, susceptibility to Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 19, 2023 | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 84 of the IRF6 protein (p.Arg84Cys). This missense change has been observed in individual(s) with popliteal pterygium syndrome (PMID: 18617879, 22488974, 25547932, 25548624). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects IRF6 function (PMID: 19036739). 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 IRF6 protein function. ClinVar contains an entry for this variant (Variation ID: 3414). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2022 | Published functional studies demonstrate p.(R84C) interferes with the DNA-binding ability of the IRF6 protein (Little et al., 2009; Kondo et al., 2002); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18617879, 23406900, 15472655, 25547932, 22488974, 25548624, 26346622, 25489771, 12219090, 28945736, 28795449, 23154410, 31488442, 19036739, 27535533) - |
IRF6-related condition Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 05, 2024 | The IRF6 c.250C>T variant is predicted to result in the amino acid substitution p.Arg84Cys. This variant has been reported to be pathogenic for IRF6-related disorders (Kosaki et al. 2012. PubMed ID: 22488974; Leslie et al. 2016. PubMed ID: 26346622; Ratbi et al. 2014. PubMed ID: 25547932; Mubungu et al. 2014. PubMed ID: 25548624). In addition, different missense variants impacting the same amino acid (p.Arg84His, p.Arg84Gly, p.Arg84Pro, and p.Arg84Leu) have also been documented to be pathogenic for IRF6-related disorders (Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php). The c.250C>T (p.Arg84Cys) variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at