rs861020

Variant names:

• chr1-209803766-A-G
• rs861020
• NM_006147.4:c.-75-1723T>C

Variant summary

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

The NM_006147.4(IRF6):​c.-75-1723T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.823 in 152,198 control chromosomes in the GnomAD database, including 51,676 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 0.82 (51676 hom., cov: 33)
• Consequence: IRF6 NM_006147.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.482
• Publications: 38 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 (AFR) allele frequency at 95% confidence interval = 0.863 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF6	NM_006147.4	c.-75-1723T>C		intron_variant	Intron 1 of 8	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.-112+2181T>C		intron_variant	Intron 1 of 6		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8	c.-75-1723T>C		intron_variant	Intron 1 of 8	1	NM_006147.4	ENSP00000355988.3
ENSG00000289700	ENST00000696133.1	c.-75-1723T>C		intron_variant	Intron 1 of 9			ENSP00000512426.1
IRF6	ENST00000542854.5	c.-112+2181T>C		intron_variant	Intron 1 of 6	2		ENSP00000440532.1
IRF6	ENST00000696134.1	n.-75-1723T>C		intron_variant	Intron 1 of 8			ENSP00000512427.1

Frequencies

GnomAD3 genomes AF: 0.823 AC: 125225 AN: 152080 Hom.: 51646 Cov.: 33

Gnomad AFR AF: 0.871

Gnomad AMI AF: 0.862

Gnomad AMR AF: 0.836

Gnomad ASJ AF: 0.841

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.783

Gnomad FIN AF: 0.760

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.804

Gnomad OTH AF: 0.834

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

GnomAD4 genome AF: 0.823 AC: 125310 AN: 152198 Hom.: 51676 Cov.: 33 AF XY: 0.820 AC XY: 61002 AN XY: 74410

African (AFR) AF: 0.871 AC: 36162 AN: 41524

American (AMR) AF: 0.835 AC: 12778 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.841 AC: 2920 AN: 3470

East Asian (EAS) AF: 0.808 AC: 4191 AN: 5184

South Asian (SAS) AF: 0.782 AC: 3773 AN: 4822

European-Finnish (FIN) AF: 0.760 AC: 8040 AN: 10580

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.804 AC: 54661 AN: 68004

Other (OTH) AF: 0.831 AC: 1755 AN: 2112

Alfa AF: 0.808 Hom.: 158119

Bravo AF: 0.829

Asia WGS AF: 0.762 AC: 2652 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.7
DANN	Benign	0.45
PhyloP100		-0.48
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: rs861020; hg19: chr1-209977111;