NM_006147.4:c.508+720T>C

Variant names:

• chr1-209794570-A-G
• rs17015218
• NM_006147.4:c.508+720T>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.508+720T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 152,210 control chromosomes in the GnomAD database, including 2,382 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 0.17 (2382 hom., cov: 33)
• Consequence: IRF6 NM_006147.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92
• Publications: 5 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, Labcorp Genetics (formerly Invitae), G2P
• IRF6-related condition

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

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF6	NM_006147.4	MANE Select	c.508+720T>C		intron	N/A	NP_006138.1	G0Z349
	IRF6	NM_001206696.2		c.223+720T>C		intron	N/A	NP_001193625.1	O14896-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF6	ENST00000367021.8	TSL:1 MANE Select	c.508+720T>C		intron	N/A	ENSP00000355988.3	O14896-1
	ENSG00000289700	ENST00000696133.1		c.508+720T>C		intron	N/A	ENSP00000512426.1	A0A8Q3SJ75
	IRF6	ENST00000863915.1		c.508+720T>C		intron	N/A	ENSP00000533974.1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25864 AN: 152092 Hom.: 2383 Cov.: 33

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.0644

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.165

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

GnomAD4 genome AF: 0.170 AC: 25873 AN: 152210 Hom.: 2382 Cov.: 33 AF XY: 0.167 AC XY: 12408 AN XY: 74438

African (AFR) AF: 0.225 AC: 9337 AN: 41510

American (AMR) AF: 0.142 AC: 2171 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 405 AN: 3468

East Asian (EAS) AF: 0.0644 AC: 334 AN: 5190

South Asian (SAS) AF: 0.214 AC: 1033 AN: 4826

European-Finnish (FIN) AF: 0.114 AC: 1214 AN: 10604

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10814 AN: 67998

Other (OTH) AF: 0.163 AC: 344 AN: 2114

Alfa AF: 0.144 Hom.: 289

Bravo AF: 0.171

Asia WGS AF: 0.143 AC: 498 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.66
PhyloP100		1.9
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: rs17015218; hg19: chr1-209967915; COSMIC: COSV65418894; COSMIC: COSV65418894;