rs1553247602

Positions:

• chr1-209788628-GC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_006147.4(IRF6):​c.1195del​(p.Ala399LeufsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRF6 NM_006147.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.32

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 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-209788628-GC-G is Pathogenic according to our data. Variant chr1-209788628-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 458680.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF6	NM_006147.4	c.1195del	p.Ala399LeufsTer3	frameshift_variant	9/9	ENST00000367021.8
IRF6	NM_001206696.2	c.910del	p.Ala304LeufsTer3	frameshift_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF6	ENST00000367021.8	c.1195del	p.Ala399LeufsTer3	frameshift_variant	9/9	1	NM_006147.4	P1
IRF6	ENST00000542854.5	c.910del	p.Ala304LeufsTer3	frameshift_variant	7/7	2
IRF6	ENST00000643798.1	c.*705del		3_prime_UTR_variant, NMD_transcript_variant	9/9
IRF6	ENST00000696134.1	c.*622del		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:2

Revision: criteria provided, single submitter

Submissions by phenotype

Van der Woude syndrome;C0265259:Popliteal pterygium syndrome;C1837213:Orofacial cleft 6, susceptibility to Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2021

- -

Van der Woude syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 16, 2017

This sequence change deletes 1 nucleotide from exon 9 of the IRF6 mRNA (c.1195delG), causing a frameshift at codon 399. This creates a premature translational stop signal in the last exon of the IRF6 mRNA (p.Ala399Leufs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 69 amino acids of the IRF6 protein. This variant has not been reported in the literature in individuals with a IRF6-related disease. A different truncation downstream of this variant (p.Arg412*) has been determined to be pathogenic, as it is one of the most common variants reported in individuals affected with Van der Woude syndrome (PMID: 12219090, 19282774, 23154523, 25784454). This suggests that deletion of this region of the IRF6 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553247602; hg19: chr1-209961973;