rs141653312

Variant names:

• chr1-209789673-C-A
• rs141653312
• NM_006147.4:c.1173G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-209789673-C-A
• chr1-209789673-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4 BP6

The NM_006147.4(IRF6):​c.1173G>T​(p.Leu391Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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). Synonymous variant affecting the same amino acid position (i.e. L391L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IRF6 NM_006147.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.04

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 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 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=0.41841626).
• BP6: Variant 1-209789673-C-A is Benign according to our data. Variant chr1-209789673-C-A is described in ClinVar as [Benign]. Clinvar id is 559495.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.1173G>T	p.Leu391Phe	missense_variant	Exon 8 of 9	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.888G>T	p.Leu296Phe	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.1173G>T	p.Leu391Phe	missense_variant	Exon 8 of 9	1	NM_006147.4	ENSP00000355988.3
ENSG00000289700	ENST00000696133.1	c.1173G>T	p.Leu391Phe	missense_variant	Exon 8 of 10			ENSP00000512426.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Orofacial cleft 10 Benign:1

-

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 0.214. Provean protein Batch - SIFT was predicted as tolerated with score 0.27. 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	0.30
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.7	.;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.078	T;T
Sift4G	Benign	0.095	T;T
Polyphen		0.25	.;B
Vest4		0.49
MutPred		0.63		.;Gain of catalytic residue at Q393 (P = 0.1265);
MVP		0.61
MPC		0.87
ClinPred		0.71	D
GERP RS		6.0
Varity_R		0.21
gMVP		0.38

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: rs141653312; hg19: chr1-209963018;