rs28942095

Positions:

• chr1-209788626-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The ENST00000367021.8(IRF6):​c.1198C>T​(p.Arg400Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R400Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRF6 ENST00000367021.8 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.11

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-209788625-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 101515.Status of the report is no_assertion_criteria_provided, 0 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, 0.979
• PP5: Variant 1-209788626-G-A is Pathogenic according to our data. Variant chr1-209788626-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3419.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-209788626-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF6	NM_006147.4	c.1198C>T	p.Arg400Trp	missense_variant	9/9	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.913C>T	p.Arg305Trp	missense_variant	7/7		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8	c.1198C>T	p.Arg400Trp	missense_variant	9/9	1	NM_006147.4	ENSP00000355988	P1
IRF6	ENST00000542854.5	c.913C>T	p.Arg305Trp	missense_variant	7/7	2		ENSP00000440532
IRF6	ENST00000643798.1	c.*708C>T		3_prime_UTR_variant, NMD_transcript_variant	9/9			ENSP00000496669
IRF6	ENST00000696134.1	c.*625C>T		3_prime_UTR_variant, NMD_transcript_variant	9/9			ENSP00000512427

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Dec 18, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 400 of the IRF6 protein (p.Arg400Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Van der Woude syndrome (PMID: 16160700, 16211254, 19282774, 20184620, 21045959). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3419). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Van der Woude syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.74
MutPred		0.86		.;Gain of catalytic residue at V398 (P = 0.1203);
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.90
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs28942095; hg19: chr1-209961971;