rs1553248247

Positions:

• chr1-209796365-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4 BP6

The NM_006147.4(IRF6):​c.362G>T​(p.Gly121Val) 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).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRF6 NM_006147.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 5.25

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IRF6. . Gene score misZ 2.7435 (greater than the threshold 3.09). Trascript score misZ 3.8897 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.362893).
• BP6: Variant 1-209796365-C-A is Benign according to our data. Variant chr1-209796365-C-A is described in ClinVar as [Benign]. Clinvar id is 559488.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF6	NM_006147.4	c.362G>T	p.Gly121Val	missense_variant	4/9	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.77G>T	p.Gly26Val	missense_variant	2/7		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8	c.362G>T	p.Gly121Val	missense_variant	4/9	1	NM_006147.4	ENSP00000355988.3
ENSG00000289700	ENST00000696133.1	c.362G>T	p.Gly121Val	missense_variant	4/10			ENSP00000512426.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Orofacial cleft 10 Benign:1

Benign, 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 benign with polyphen score 0.051. 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 and was not found in Brazillian control population without craniofacial anomalies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;T;T
Eigen	Benign	-0.051
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.4	.;L;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D;T;D
Sift4G	Benign	0.082	T;T;.
Polyphen		0.030	.;B;.
Vest4		0.58
MutPred		0.34		.;Gain of catalytic residue at G121 (P = 0.0078);Gain of catalytic residue at G121 (P = 0.0078);
MVP		0.75
MPC		1.5
ClinPred		0.68	D
GERP RS		5.6
Varity_R		0.25
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1553248247; hg19: chr1-209969710;