rs1553248180

Variant names:

• chr1-209795341-A-C
• rs1553248180
• NM_006147.4:c.457T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BP6

The NM_006147.4(IRF6):​c.457T>G​(p.Ser153Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S153L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRF6 NM_006147.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 5.54

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 Uncertain_significance. Variant got 0 ACMG points.

• 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 orofacial cleft 6, susceptibility to, van der Woude syndrome, autosomal dominant popliteal pterygium syndrome, tooth agenesis, van der Woude syndrome 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22254092).
• BP6: Variant 1-209795341-A-C is Benign according to our data. Variant chr1-209795341-A-C is described in ClinVar as [Benign]. Clinvar id is 559490.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF6	NM_006147.4	c.457T>G	p.Ser153Ala	missense_variant	Exon 5 of 9	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.172T>G	p.Ser58Ala	missense_variant	Exon 3 of 7		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8	c.457T>G	p.Ser153Ala	missense_variant	Exon 5 of 9	1	NM_006147.4	ENSP00000355988.3
ENSG00000289700	ENST00000696133.1	c.457T>G	p.Ser153Ala	missense_variant	Exon 5 of 10			ENSP00000512426.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Orofacial cleft 10 Benign:1

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: case-control

In silico analysis revealed polyphen prediction benign with polyphen score 0.114. Provean protein Batch - SIFT was predicted as tolerated with score 0.82. Mutation tester predicted disease causing. This rare variation was found just in a patient witn cleft and was not found in Brazillian control population without craniofacial anomalies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	.;T;T
Eigen	Benign	-0.043
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Uncertain	-0.082	T
MutationAssessor	Benign	1.6	.;L;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.34	N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.45	T;T;T
Sift4G	Benign	0.98	T;T;.
Polyphen		0.070	.;B;.
Vest4		0.38
MutPred		0.26		.;Loss of phosphorylation at S153 (P = 0.0522);Loss of phosphorylation at S153 (P = 0.0522);
MVP		0.87
MPC		0.036
ClinPred		0.35	T
GERP RS		5.4
Varity_R		0.060
gMVP		0.21

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: rs1553248180; hg19: chr1-209968686;