rs2236909

Variant names:

• chr1-209798310-A-G
• rs2236909
• NM_006147.4:c.175-1758T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000367021.8(IRF6):​c.175-1758T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 152,062 control chromosomes in the GnomAD database, including 10,518 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.37 (10518 hom., cov: 33)
• Consequence: IRF6 ENST00000367021.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.456
• Publications: 11 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000367021.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF6	NM_006147.4	MANE Select	c.175-1758T>C		intron	N/A	NP_006138.1
	IRF6	NM_001206696.2		c.-111-1758T>C		intron	N/A	NP_001193625.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF6	ENST00000367021.8	TSL:1 MANE Select	c.175-1758T>C		intron	N/A	ENSP00000355988.3
	ENSG00000289700	ENST00000696133.1		c.175-1758T>C		intron	N/A	ENSP00000512426.1
	IRF6	ENST00000542854.5	TSL:2	c.-111-1758T>C		intron	N/A	ENSP00000440532.1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55492 AN: 151944 Hom.: 10514 Cov.: 33

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.394

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.566

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.361

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

GnomAD4 genome AF: 0.365 AC: 55518 AN: 152062 Hom.: 10518 Cov.: 33 AF XY: 0.369 AC XY: 27438 AN XY: 74334

African (AFR) AF: 0.280 AC: 11617 AN: 41464

American (AMR) AF: 0.495 AC: 7562 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1111 AN: 3470

East Asian (EAS) AF: 0.566 AC: 2924 AN: 5170

South Asian (SAS) AF: 0.431 AC: 2078 AN: 4824

European-Finnish (FIN) AF: 0.365 AC: 3864 AN: 10580

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.370 AC: 25143 AN: 67962

Other (OTH) AF: 0.356 AC: 754 AN: 2116

Alfa AF: 0.375 Hom.: 1714

Bravo AF: 0.371

Asia WGS AF: 0.425 AC: 1481 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.8
DANN	Benign	0.70
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism (auto)

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: rs2236909; hg19: chr1-209971655; COSMIC: COSV65418926;