NM_006147.4:c.175-1588A>C

Variant names:

• chr1-209798140-T-G
• rs2236906
• NM_006147.4:c.175-1588A>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.175-1588A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 152,014 control chromosomes in the GnomAD database, including 12,428 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 0.40 (12428 hom., cov: 32)
• Consequence: IRF6 NM_006147.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.15
• Publications: 13 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006147.4. 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.175-1588A>C		intron	N/A	NP_006138.1
	IRF6	NM_001206696.2		c.-111-1588A>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.175-1588A>C		intron	N/A	ENSP00000355988.3
	ENSG00000289700	ENST00000696133.1		c.175-1588A>C		intron	N/A	ENSP00000512426.1
	IRF6	ENST00000542854.5	TSL:2	c.-111-1588A>C		intron	N/A	ENSP00000440532.1

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60573 AN: 151896 Hom.: 12418 Cov.: 32

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.426

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

GnomAD4 genome AF: 0.399 AC: 60620 AN: 152014 Hom.: 12428 Cov.: 32 AF XY: 0.395 AC XY: 29319 AN XY: 74302

African (AFR) AF: 0.389 AC: 16103 AN: 41444

American (AMR) AF: 0.316 AC: 4828 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 1777 AN: 3466

East Asian (EAS) AF: 0.242 AC: 1250 AN: 5164

South Asian (SAS) AF: 0.348 AC: 1675 AN: 4818

European-Finnish (FIN) AF: 0.394 AC: 4162 AN: 10562

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.432 AC: 29364 AN: 67960

Other (OTH) AF: 0.428 AC: 903 AN: 2112

Alfa AF: 0.423 Hom.: 7075

Bravo AF: 0.391

Asia WGS AF: 0.320 AC: 1112 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.52
DANN	Benign	0.46
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2236906; hg19: chr1-209971485;