rs1553247688

chr1-209789671-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_006147.4(IRF6):c.1175T>G(p.Val392Gly) 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 (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IRF6 NM_006147.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 8.49

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, IRF6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF6	NM_006147.4	c.1175T>G	p.Val392Gly	missense_variant	8/9	ENST00000367021.8
IRF6	NM_001206696.2	c.890T>G	p.Val297Gly	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF6	ENST00000367021.8	c.1175T>G	p.Val392Gly	missense_variant	8/9	1	NM_006147.4	P1
IRF6	ENST00000542854.5	c.890T>G	p.Val297Gly	missense_variant	6/7	2
IRF6	ENST00000643798.1	c.*685T>G		3_prime_UTR_variant, NMD_transcript_variant	8/9
IRF6	ENST00000696134.1	c.*602T>G		3_prime_UTR_variant, NMD_transcript_variant	8/9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Orofacial cleft 10 Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

Pharmacology and Genetics Laboratory, Bauru School of Dentistry, University of Sao Paulo

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In silico analysis revealed polyphen prediction probably damage with polyphen score 1.000. Provean protein Batch - SIFT was predicted as damaging with score 0.004. Mutation tester predicted disease causing. This rare variation was found just in a patient witn cleft with dental agenesis and was not found in Brazillian control population without craniofacial anomalies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.68
MutPred		0.74		.;Loss of stability (P = 0.0039);
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.95
gMVP		0.92

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: rs1553247688; hg19: chr1-209963016;