rs1553247688

Variant names:

• chr1-209789671-A-C
• rs1553247688
• NM_006147.4:c.1175T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 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
• Publications: 0 publications found

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]

IRF6 Gene-Disease associations (from GenCC):

• autosomal dominant popliteal pterygium syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• IRF6-related condition

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• van der Woude syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• popliteal pterygium syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• van der Woude syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• orofacial cleft 6, susceptibility to

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000289700 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_006147.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the IRF6 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 2.7435 (below the threshold of 3.09). Trascript score misZ: 3.8897 (above the threshold of 3.09). GenCC associations: The gene is linked to van der Woude syndrome 1, van der Woude syndrome, autosomal dominant popliteal pterygium syndrome, orofacial cleft 6, susceptibility to, tooth agenesis, IRF6-related condition, popliteal pterygium syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF6	NM_006147.4	c.1175T>G	p.Val392Gly	missense_variant	Exon 8 of 9	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.890T>G	p.Val297Gly	missense_variant	Exon 6 of 7		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8	c.1175T>G	p.Val392Gly	missense_variant	Exon 8 of 9	1	NM_006147.4	ENSP00000355988.3
ENSG00000289700	ENST00000696133.1	c.1175T>G	p.Val392Gly	missense_variant	Exon 8 of 10			ENSP00000512426.1

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

-

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: case-control

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
DEOGEN2	Pathogenic	0.97	.;D
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
MutationAssessor	Pathogenic	3.4	.;M
PhyloP100		8.5
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
Mutation Taster		=26/74	disease causing

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

Other links and lift over

dbSNP: rs1553247688; hg19: chr1-209963016;