chr1-209788455-TG-T

Variant names:

• chr1-209788455-TG-T
• rs1553247577
• NM_006147.4:c.1368delC

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_006147.4(IRF6):​c.1368delC​(p.Ser457AlafsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IRF6 NM_006147.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.52
• Publications: 0 publications found

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]

IRF6 Gene-Disease associations (from GenCC):

• autosomal dominant popliteal pterygium syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• IRF6-related condition

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• van der Woude syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• popliteal pterygium syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• van der Woude syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• orofacial cleft 6, susceptibility to

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000289700 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 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 0.0256 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF6	NM_006147.4	c.1368delC	p.Ser457AlafsTer34	frameshift_variant	Exon 9 of 9	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.1083delC	p.Ser362AlafsTer34	frameshift_variant	Exon 7 of 7		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8	c.1368delC	p.Ser457AlafsTer34	frameshift_variant	Exon 9 of 9	1	NM_006147.4	ENSP00000355988.3
ENSG00000289700	ENST00000696133.1	c.1368delC	p.Ser457AlafsTer92	frameshift_variant	Exon 9 of 10			ENSP00000512426.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458686 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725894

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109322

Other (OTH) AF: 0.00 AC: 0 AN: 60254

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Popliteal pterygium syndrome;C1837213:Orofacial cleft 6, susceptibility to;C4551864:Van der Woude syndrome 1 Uncertain:1

Oct 18, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes 1 nucleotide in exon 9 of the IRF6 mRNA (c.1368delC), causing a frameshift at codon 457. This is not anticipated to result in nonsense mediated decay but it is expected to expected to alter the last 11 amino acids and extend the IRF6 protein by an additional 22 amino acids (p.Ser457Alafs*34). This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with IRF6-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the disrupted amino acids is currently unknown. Multiple downstream frameshift variants that results in an extended protein product have been reported in individuals affected with van der Woude syndrome (PMID: PMID: 12219090, 23154523, 19282774). However these variants create a frameshifts and extensions that are different from the one created by this variant. Therefore the effect of this particular frameshift and extension is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.5

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

Other links and lift over

dbSNP: rs1553247577; hg19: chr1-209961800;