rs1553248641

Positions:

• chr1-209801389-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_006147.4(IRF6):​c.25C>T​(p.Arg9Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,682 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R9Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IRF6 NM_006147.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.37

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]

ENSG00000289700 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006147.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-209801388-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449040.Status of the report is criteria_provided_single_submitter, 1 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, 0.986
• PP5: Variant 1-209801389-G-A is Pathogenic according to our data. Variant chr1-209801389-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-209801389-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF6	NM_006147.4	c.25C>T	p.Arg9Trp	missense_variant	3/9	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.-112+4558C>T		intron_variant			NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8	c.25C>T	p.Arg9Trp	missense_variant	3/9	1	NM_006147.4	ENSP00000355988.3
ENSG00000289700	ENST00000696133.1	c.25C>T	p.Arg9Trp	missense_variant	3/10			ENSP00000512426.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458682 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725400

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: 0.0000189

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

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

Apr 11, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg9 amino acid residue in IRF6. Other variant(s) that disrupt this residue have been observed in individuals with IRF6-related conditions (PMID: 19282774), which suggests that this may be a clinically significant amino acid residue. 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: 449039). This missense change has been observed in individuals with Van der Woude syndrome (PMID: 15472655, 19449419, 31468312; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 9 of the IRF6 protein (p.Arg9Trp). -

IRF6-related condition Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2024

The IRF6 c.25C>T variant is predicted to result in the amino acid substitution p.Arg9Trp. This variant has been reported in individuals with Van der Woude syndrome (Matsuzawa et al. 2004. PubMed ID: 15472655; Jehee et al. 2009. PubMed ID: 19449419). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 25, 2017

The R9W variant in the IRF6 gene has previously been reported in association with van der Woude syndrome (Matsuzaka et al., 2004; Jehee et al., 2009). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R9W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and located within the DNA-binding domain (Little et al., 2009). In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available evidence, R9W is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded. -

Van der Woude syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Oct 04, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.2	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.92		Gain of catalytic residue at P12 (P = 0.0189);Gain of catalytic residue at P12 (P = 0.0189);
MVP		0.99
MPC		2.4
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.93
gMVP		0.93

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

Other links and lift over

dbSNP: rs1553248641; hg19: chr1-209974734; COSMIC: COSV65419612;