rs2073485

Variant names:

• chr1-209789449-G-A
• rs2073485
• NM_006147.4:c.1179+218C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006147.4(IRF6):​c.1179+218C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 151,774 control chromosomes in the GnomAD database, including 4,024 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.22 (4024 hom., cov: 32)
• Consequence: IRF6 NM_006147.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.409
• Publications: 17 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-209789449-G-A is Benign according to our data. Variant chr1-209789449-G-A is described in ClinVar as Benign. ClinVar VariationId is 1274820.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF6	NM_006147.4	c.1179+218C>T		intron_variant	Intron 8 of 8	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2	c.894+218C>T		intron_variant	Intron 6 of 6		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8	c.1179+218C>T		intron_variant	Intron 8 of 8	1	NM_006147.4	ENSP00000355988.3
ENSG00000289700	ENST00000696133.1	c.1179+218C>T		intron_variant	Intron 8 of 9			ENSP00000512426.1

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32763 AN: 151658 Hom.: 4020 Cov.: 32

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.203

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

GnomAD4 genome AF: 0.216 AC: 32785 AN: 151774 Hom.: 4024 Cov.: 32 AF XY: 0.219 AC XY: 16249 AN XY: 74202

African (AFR) AF: 0.235 AC: 9723 AN: 41346

American (AMR) AF: 0.325 AC: 4959 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 460 AN: 3472

East Asian (EAS) AF: 0.472 AC: 2437 AN: 5168

South Asian (SAS) AF: 0.309 AC: 1486 AN: 4808

European-Finnish (FIN) AF: 0.127 AC: 1341 AN: 10522

Middle Eastern (MID) AF: 0.185 AC: 54 AN: 292

European-Non Finnish (NFE) AF: 0.172 AC: 11706 AN: 67886

Other (OTH) AF: 0.201 AC: 424 AN: 2108

Alfa AF: 0.184 Hom.: 1745

Bravo AF: 0.229

Asia WGS AF: 0.330 AC: 1148 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

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	-0.80
CADD	Benign	2.1
DANN	Benign	0.68
PhyloP100		-0.41
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: rs2073485; hg19: chr1-209962794;