rs2294408

Variant names:

• chr1-209800204-G-A
• rs2294408
• NM_006147.4:c.174+1036C>T

Variant summary

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

The NM_006147.4(IRF6):​c.174+1036C>T 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 152,042 control chromosomes in the GnomAD database, including 10,536 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 (10536 hom., cov: 32)
• Consequence: IRF6 NM_006147.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.729
• Publications: 7 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF6	NM_006147.4	c.174+1036C>T		intron_variant	Intron 3 of 8	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.-111-3652C>T		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.174+1036C>T		intron_variant	Intron 3 of 8	1	NM_006147.4	ENSP00000355988.3
ENSG00000289700	ENST00000696133.1	c.174+1036C>T		intron_variant	Intron 3 of 9			ENSP00000512426.1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55512 AN: 151924 Hom.: 10532 Cov.: 32

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.568

Gnomad SAS AF: 0.430

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: 55538 AN: 152042 Hom.: 10536 Cov.: 32 AF XY: 0.369 AC XY: 27455 AN XY: 74314

African (AFR) AF: 0.280 AC: 11613 AN: 41448

American (AMR) AF: 0.496 AC: 7575 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1117 AN: 3468

East Asian (EAS) AF: 0.567 AC: 2922 AN: 5156

South Asian (SAS) AF: 0.430 AC: 2077 AN: 4826

European-Finnish (FIN) AF: 0.365 AC: 3855 AN: 10556

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

European-Non Finnish (NFE) AF: 0.370 AC: 25163 AN: 67988

Other (OTH) AF: 0.357 AC: 753 AN: 2112

Alfa AF: 0.356 Hom.: 1192

Bravo AF: 0.371

Asia WGS AF: 0.426 AC: 1482 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.77
DANN	Benign	0.68
PhyloP100		-0.73
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: rs2294408; hg19: chr1-209973549; COSMIC: COSV65418934;