rs1553247899

chr1-209792422-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_006147.4(IRF6):c.514C>T(p.Pro172Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 6.28

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, IRF6

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF6	NM_006147.4	c.514C>T	p.Pro172Ser	missense_variant	6/9	ENST00000367021.8
IRF6	NM_001206696.2	c.229C>T	p.Pro77Ser	missense_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF6	ENST00000367021.8	c.514C>T	p.Pro172Ser	missense_variant	6/9	1	NM_006147.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Orofacial cleft 10;C1970308:Selective tooth agenesis 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 possibly damage with polyphen score 0.949. Provean protein Batch - SIFT was predicted as tolerated with score 0.43. 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	Benign	0.097
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Uncertain	0.0017	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.29	N;N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.019	D;T;D
Sift4G	Benign	0.17	T;T;.
Polyphen		0.92	.;P;.
Vest4		0.16
MutPred		0.30		.;Gain of catalytic residue at P172 (P = 0.0029);Gain of catalytic residue at P172 (P = 0.0029);
MVP		0.60
MPC		0.15
ClinPred		0.83	D
GERP RS		5.8
Varity_R		0.070
gMVP		0.39

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: rs1553247899; hg19: chr1-209965767;