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

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

IRF6
ENST00000367021.8 missense

Scores

16
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 5.15
Variant links:
Genes affected
IRF6 (HGNC:6121): (interferon regulatory factor 6) This gene encodes a member of the interferon regulatory transcription factor (IRF) family. Family members share a highly-conserved N-terminal helix-turn-helix DNA-binding domain and a less conserved C-terminal protein-binding domain. The encoded protein may be a transcriptional activator. Mutations in this gene can cause van der Woude syndrome and popliteal pterygium syndrome. Mutations in this gene are also associated with non-syndromic orofacial cleft type 6. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2011]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000367021.8
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-209796476-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IRF6. . Gene score misZ 2.7435 (greater than the threshold 3.09). Trascript score misZ 3.8897 (greater than threshold 3.09). GenCC has associacion of gene with orofacial cleft 6, susceptibility to, van der Woude syndrome, autosomal dominant popliteal pterygium syndrome, tooth agenesis, van der Woude syndrome 1.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant 1-209796477-G-A is Pathogenic according to our data. Variant chr1-209796477-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
IRF6NM_006147.4 linkuse as main transcriptc.250C>T p.Arg84Cys missense_variant 4/9 ENST00000367021.8 NP_006138.1
IRF6NM_001206696.2 linkuse as main transcriptc.-36C>T 5_prime_UTR_variant 2/7 NP_001193625.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
IRF6ENST00000367021.8 linkuse as main transcriptc.250C>T p.Arg84Cys missense_variant 4/91 NM_006147.4 ENSP00000355988 P1O14896-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461674
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727142
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal dominant popliteal pterygium syndrome Pathogenic:1Other:1
not provided, no classification providedliterature onlyGeneReviews-Most commonly seen in persons with popliteal pterygium syndrome -
Pathogenic, criteria provided, single submitterclinical testingDepartment of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized MedicineMay 26, 2023- -
Popliteal pterygium syndrome Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 01, 2002- -
Van der Woude syndrome;C0265259:Popliteal pterygium syndrome;C1837213:Orofacial cleft 6, susceptibility to Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 19, 2023This 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 submitterclinical testingGeneDxJan 17, 2022Published 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 providedclinical testingPreventionGenetics, part of Exact SciencesApr 05, 2024The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.98
D;D
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.1
H;.
MutationTaster
Benign
1.0
A;A
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-7.2
D;D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;.
Vest4
0.87
MutPred
0.96
Loss of MoRF binding (P = 0.0015);Loss of MoRF binding (P = 0.0015);
MVP
0.99
MPC
2.7
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.90
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121434226; hg19: chr1-209969822; COSMIC: COSV65419483; COSMIC: COSV65419483; API