rs1553247744

Positions:

• chr1-209790500-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_006147.4(IRF6):​c.1055T>G​(p.Leu352Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IRF6 NM_006147.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.73

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. GenCC has associacion of the 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, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF6	NM_006147.4	c.1055T>G	p.Leu352Arg	missense_variant	7/9	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.770T>G	p.Leu257Arg	missense_variant	5/7		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8	c.1055T>G	p.Leu352Arg	missense_variant	7/9	1	NM_006147.4	ENSP00000355988.3
ENSG00000289700	ENST00000696133.1	c.1055T>G	p.Leu352Arg	missense_variant	7/10			ENSP00000512426.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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

Nov 19, 2024

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 352 of the IRF6 protein (p.Leu352Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of van der Woude syndrome (internal data). ClinVar contains an entry for this variant (Variation ID: 464461). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IRF6 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	.;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.93
MutPred		0.78		.;Gain of catalytic residue at L352 (P = 0.0222);
MVP		0.97
MPC		2.0
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.94
gMVP		0.96

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: rs1553247744; hg19: chr1-209963845;