chr1-209796467-A-G
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong
The NM_006147.4(IRF6):c.260T>C(p.Leu87Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L87F) has been classified as Pathogenic.
Frequency
Consequence
NM_006147.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
IRF6 | NM_006147.4 | c.260T>C | p.Leu87Pro | missense_variant | 4/9 | ENST00000367021.8 | NP_006138.1 | |
IRF6 | NM_001206696.2 | c.-26T>C | 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.260T>C | p.Leu87Pro | missense_variant | 4/9 | 1 | NM_006147.4 | ENSP00000355988.3 | ||
ENSG00000289700 | ENST00000696133.1 | c.260T>C | p.Leu87Pro | missense_variant | 4/10 | ENSP00000512426.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Van der Woude syndrome;C0265259:Popliteal pterygium syndrome;C1837213:Orofacial cleft 6, susceptibility to Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 10, 2017 | 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. A different missense substitutions at this codon (p.Leu87Phe) has been reported in individuals affected with Van der Woude syndrome (VWS) (PMID: 19282774). This suggests that the leucine residue may be critical for IRF6 protein function Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with IRF6-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 87 of the IRF6 protein (p.Leu87Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. - |
IRF6-related condition Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 18, 2024 | The IRF6 c.260T>C variant is predicted to result in the amino acid substitution p.Leu87Pro. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. An alternative nucleotide change affecting the same amino acid (c.259C>T, p.Leu87Phe) has been reported in individuals with Van der Woude syndrome, including affected family member(s) (de Lima et al. 2009. PubMed ID: 19282774; Family 6 in Yu et al. 2020. PubMed ID: 32108996). Although we suspect that the c.260T>C (p.Leu87Pro) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at