rs41303263

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_006147.4(IRF6):c.759T>C(p.Tyr253Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 1,614,166 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0037 ( 8 hom. )

Consequence

IRF6
NM_006147.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0130

Publications

2 publications found

Variant links:

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)

IRF6 links:

ENSG00000289700 (HGNC:):

ENSG00000289700 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 1-209790796-A-G is Benign according to our data. Variant chr1-209790796-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.013 with no splicing effect.

BS2

High AC in GnomAd4 at 360 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF6	NM_006147.4 link	c.759T>C	p.Tyr253Tyr	synonymous_variant	Exon 7 of 9	ENST00000367021.8	NP_006138.1	O14896-1G0Z349
IRF6	NM_001206696.2 link	c.474T>C	p.Tyr158Tyr	synonymous_variant	Exon 5 of 7		NP_001193625.1	O14896-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8 link	c.759T>C	p.Tyr253Tyr	synonymous_variant	Exon 7 of 9	1	NM_006147.4	ENSP00000355988.3		O14896-1
ENSG00000289700	ENST00000696133.1 link	c.759T>C	p.Tyr253Tyr	synonymous_variant	Exon 7 of 10			ENSP00000512426.1		A0A8Q3SJ75

Frequencies

GnomAD3 genomes

AF:

0.00237

AC:

360

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00346

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00392

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00252

AC:

633

AN:

250982

AF XY:

0.00257

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.000868

Gnomad ASJ exome

AF:

0.00279

Gnomad EAS exome

AF:

0.00315

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00408

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00374

AC:

5470

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00363

AC XY:

2640

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33478

American (AMR)

AF:

0.000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

26134

East Asian (EAS)

AF:

0.00219

AC:

AN:

39700

South Asian (SAS)

AF:

0.000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000618

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000349

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00450

AC:

5003

AN:

1112012

Other (OTH)

AF:

0.00272

AC:

164

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

357

714

1072

1429

1786

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

392

588

784

980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00236

AC:

360

AN:

152320

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

171

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000794

AC:

AN:

41582

American (AMR)

AF:

0.000980

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3464

East Asian (EAS)

AF:

0.00347

AC:

AN:

5186

South Asian (SAS)

AF:

0.00145

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00392

AC:

267

AN:

68026

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00269

Hom.:

Bravo

AF:

0.00254

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00294

EpiControl

AF:

0.00362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

IRF6: BP4, BP7, BS1 -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Van der Woude syndrome;C0265259:Popliteal pterygium syndrome;C1837213:Orofacial cleft 6, susceptibility to

Benign:1

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Orofacial cleft 6, susceptibility to

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Van der Woude syndrome 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely 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

-0.64

CADD

Benign

5.4

(source)

DANN

Benign

0.75

PhyloP100

-0.013

Mutation Taster

=83/17

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over