rs28942093

Positions:

• chr1-209801409-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

The NM_006147.4(IRF6):​c.5C>T​(p.Ala2Val) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRF6 NM_006147.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.41

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, IRF6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774
• PP5: Variant 1-209801409-G-A is Pathogenic according to our data. Variant chr1-209801409-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3416.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF6	NM_006147.4	c.5C>T	p.Ala2Val	missense_variant	3/9	ENST00000367021.8
IRF6	NM_001206696.2	c.-112+4538C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF6	ENST00000367021.8	c.5C>T	p.Ala2Val	missense_variant	3/9	1	NM_006147.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Van der Woude syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.017	D;.
Polyphen		0.94	P;.
Vest4		0.77
MutPred		0.41		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		0.98
MPC		1.6
ClinPred		0.90	D
GERP RS		5.3
Varity_R		0.17
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs28942093; hg19: chr1-209974754; COSMIC: COSV65420110;