rs1057520168

Positions:

• chr1-209788593-TGAAATCACCA-T

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.1221_1230del​(p.Gly408HisfsTer26) 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:1
• Conservation: PhyloP100: 7.42

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. Fraction of 0.13 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-209788593-TGAAATCACCA-T is Pathogenic according to our data. Variant chr1-209788593-TGAAATCACCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 377224.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF6	NM_006147.4	c.1221_1230del	p.Gly408HisfsTer26	frameshift_variant	9/9	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.936_945del	p.Gly313HisfsTer26	frameshift_variant	7/7		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8	c.1221_1230del	p.Gly408HisfsTer26	frameshift_variant	9/9	1	NM_006147.4	ENSP00000355988	P1
IRF6	ENST00000542854.5	c.936_945del	p.Gly313HisfsTer26	frameshift_variant	7/7	2		ENSP00000440532
IRF6	ENST00000643798.1	c.*731_*740del		3_prime_UTR_variant, NMD_transcript_variant	9/9			ENSP00000496669
IRF6	ENST00000696134.1	c.*648_*657del		3_prime_UTR_variant, NMD_transcript_variant	9/9			ENSP00000512427

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jul 08, 2016

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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: rs1057520168; hg19: chr1-209961938;