rs121434226

Positions:

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

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]

IRF6 links:

Genome browser will be placed here

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
IRF6	NM_006147.4 linkuse as main transcript	c.250C>T	p.Arg84Cys	missense_variant	4/9	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2 linkuse as main transcript	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 linkuse as main transcript	c.250C>T	p.Arg84Cys	missense_variant	4/9	1	NM_006147.4	ENSP00000355988	P1	O14896-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461674

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

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.:

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 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.85

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over