NM_006147.4:c.508+224G>A

Variant names:

• chr1-209795066-C-T
• rs2013196
• NM_006147.4:c.508+224G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006147.4(IRF6):​c.508+224G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 152,176 control chromosomes in the GnomAD database, including 2,086 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.15 (2086 hom., cov: 33)
• Consequence: IRF6 NM_006147.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.471
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-209795066-C-T is Benign according to our data. Variant chr1-209795066-C-T is described in ClinVar as [Benign]. Clinvar id is 1246145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF6	NM_006147.4	c.508+224G>A		intron_variant	Intron 5 of 8	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.223+224G>A		intron_variant	Intron 3 of 6		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8	c.508+224G>A		intron_variant	Intron 5 of 8	1	NM_006147.4	ENSP00000355988.3
ENSG00000289700	ENST00000696133.1	c.508+224G>A		intron_variant	Intron 5 of 9			ENSP00000512426.1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22759 AN: 152058 Hom.: 2088 Cov.: 33

Gnomad AFR AF: 0.0467

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.0917

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.158

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

GnomAD4 genome AF: 0.150 AC: 22761 AN: 152176 Hom.: 2086 Cov.: 33 AF XY: 0.151 AC XY: 11205 AN XY: 74382

African (AFR) AF: 0.0468 AC: 1942 AN: 41540

American (AMR) AF: 0.171 AC: 2611 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 651 AN: 3472

East Asian (EAS) AF: 0.0911 AC: 472 AN: 5180

South Asian (SAS) AF: 0.121 AC: 582 AN: 4822

European-Finnish (FIN) AF: 0.239 AC: 2520 AN: 10562

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.198 AC: 13439 AN: 67990

Other (OTH) AF: 0.156 AC: 330 AN: 2114

Alfa AF: 0.164 Hom.: 416

Bravo AF: 0.143

Asia WGS AF: 0.0920 AC: 319 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.0
DANN	Benign	0.57
PhyloP100		0.47
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: rs2013196; hg19: chr1-209968411;