rs587776569

Variant names:

• chr1-209790667-GTCCAGCAGCTTGCTAGTG-T
• rs587776569
• NM_006147.4:c.870_888delCACTAGCAAGCTGCTGGACinsA

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM4 PP2 PP3 PP5

The NM_006147.4(IRF6):​c.870_888delCACTAGCAAGCTGCTGGACinsA​(p.Phe290_Asp296delinsLeu) variant causes a missense, conservative inframe deletion 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 (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IRF6 NM_006147.4 missense, conservative_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.73

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_006147.4.
• 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.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 1-209790667-GTCCAGCAGCTTGCTAGTG-T is Pathogenic according to our data. Variant chr1-209790667-GTCCAGCAGCTTGCTAGTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 3412.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.870_888delCACTAGCAAGCTGCTGGACinsA	p.Phe290_Asp296delinsLeu	missense_variant, conservative_inframe_deletion	Exon 7 of 9	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.585_603delCACTAGCAAGCTGCTGGACinsA	p.Phe195_Asp201delinsLeu	missense_variant, conservative_inframe_deletion	Exon 5 of 7		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8	c.870_888delCACTAGCAAGCTGCTGGACinsA	p.Phe290_Asp296delinsLeu	missense_variant, conservative_inframe_deletion	Exon 7 of 9	1	NM_006147.4	ENSP00000355988.3
ENSG00000289700	ENST00000696133.1	c.870_888delCACTAGCAAGCTGCTGGACinsA	p.Phe290_Asp296delinsLeu	missense_variant, conservative_inframe_deletion	Exon 7 of 10			ENSP00000512426.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Van der Woude syndrome 1 Pathogenic:1

Oct 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587776569; hg19: chr1-209964012;