rs387906968

chr1-209788553-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_006147.4(IRF6):c.1271C>T(p.Ser424Leu) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S424A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRF6 NM_006147.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.27

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 Likely_pathogenic. Variant got 6 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, 0.918
• PP5: Variant 1-209788553-G-A is Pathogenic according to our data. Variant chr1-209788553-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30654.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.1271C>T	p.Ser424Leu	missense_variant	9/9	ENST00000367021.8
IRF6	NM_001206696.2	c.986C>T	p.Ser329Leu	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF6	ENST00000367021.8	c.1271C>T	p.Ser424Leu	missense_variant	9/9	1	NM_006147.4	P1
IRF6	ENST00000542854.5	c.986C>T	p.Ser329Leu	missense_variant	7/7	2
IRF6	ENST00000643798.1	c.*781C>T		3_prime_UTR_variant, NMD_transcript_variant	9/9
IRF6	ENST00000696134.1	c.*698C>T		3_prime_UTR_variant, NMD_transcript_variant	9/9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Popliteal pterygium syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.4	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.94
MutPred		0.58		.;Loss of disorder (P = 0.0367);
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.62
gMVP		0.88

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: rs387906968; hg19: chr1-209961898; COSMIC: COSV54214032; COSMIC: COSV54214032;