rs2235371

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_006147.4(IRF6):c.820G>A(p.Val274Ile) variant causes a missense change. The variant allele was found at a frequency of 0.037 in 1,614,178 control chromosomes in the GnomAD database, including 6,385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 802 hom., cov: 33)

Exomes 𝑓: 0.036 ( 5583 hom. )

Consequence

IRF6
NM_006147.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.84

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 links:

ENSG00000289700 (HGNC:):

ENSG00000289700 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the IRF6 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 2.7435 (below the threshold of 3.09). Trascript score misZ: 3.8897 (above the threshold of 3.09). GenCC associations: The gene is linked to orofacial cleft 6, susceptibility to, van der Woude syndrome, autosomal dominant popliteal pterygium syndrome, tooth agenesis, van der Woude syndrome 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020831823).

BP6

Variant 1-209790735-C-T is Benign according to our data. Variant chr1-209790735-C-T is described in ClinVar as [Benign]. Clinvar id is 259928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF6	NM_006147.4 link	c.820G>A	p.Val274Ile	missense_variant	Exon 7 of 9	ENST00000367021.8	NP_006138.1	O14896-1G0Z349
IRF6	NM_001206696.2 link	c.535G>A	p.Val179Ile	missense_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.820G>A	p.Val274Ile	missense_variant	Exon 7 of 9	1	NM_006147.4	ENSP00000355988.3		O14896-1
ENSG00000289700	ENST00000696133.1 link	c.820G>A	p.Val274Ile	missense_variant	Exon 7 of 10			ENSP00000512426.1		A0A8Q3SJ75

Frequencies

GnomAD3 genomes

AF:

0.0447

AC:

6800

AN:

152176

Hom.:

797

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00709

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.181

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.406

Gnomad SAS

AF:

0.0921

Gnomad FIN

AF:

0.0125

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0134

Gnomad OTH

AF:

0.0368

GnomAD3 exomes

AF:

0.0867

AC:

21729

AN:

250644

Hom.:

3073

AF XY:

0.0783

AC XY:

10603

AN XY:

135492

show subpopulations

Gnomad AFR exome

AF:

0.00579

Gnomad AMR exome

AF:

0.263

Gnomad ASJ exome

AF:

0.0183

Gnomad EAS exome

AF:

0.416

Gnomad SAS exome

AF:

0.0800

Gnomad FIN exome

AF:

0.0131

Gnomad NFE exome

AF:

0.0144

Gnomad OTH exome

AF:

0.0563

GnomAD4 exome

AF:

0.0362

AC:

52859

AN:

1461884

Hom.:

5583

Cov.:

AF XY:

0.0362

AC XY:

26347

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00490

Gnomad4 AMR exome

AF:

0.253

Gnomad4 ASJ exome

AF:

0.0188

Gnomad4 EAS exome

AF:

0.413

Gnomad4 SAS exome

AF:

0.0793

Gnomad4 FIN exome

AF:

0.0146

Gnomad4 NFE exome

AF:

0.0128

Gnomad4 OTH exome

AF:

0.0435

GnomAD4 genome

AF:

0.0447

AC:

6811

AN:

152294

Hom.:

802

Cov.:

AF XY:

0.0512

AC XY:

3812

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00707

Gnomad4 AMR

AF:

0.182

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.406

Gnomad4 SAS

AF:

0.0915

Gnomad4 FIN

AF:

0.0125

Gnomad4 NFE

AF:

0.0134

Gnomad4 OTH

AF:

0.0369

Alfa

AF:

0.0291

Hom.:

918

Bravo

AF:

0.0572

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.0138

AC:

119

ExAC

AF:

0.0765

AC:

9287

Asia WGS

AF:

0.185

AC:

643

AN:

3478

EpiCase

AF:

0.0117

EpiControl

AF:

0.0123

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20799332, 23949966, 19115793, 20121942, 18278815, 19419265, 19036739, 15994871, 15317890, 30462859) -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: 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

Jan 23, 2025

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: 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Van der Woude syndrome 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

.;D;T

Eigen

Uncertain

0.64

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

D;D;D

MetaRNN

Benign

0.0021

T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.3

.;L;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.42

N;N;N

REVEL

Uncertain

0.39

Sift

Uncertain

0.0040

D;T;T

Sift4G

Uncertain

0.019

D;T;.

Polyphen

0.98

.;D;.

Vest4

0.17

MPC

1.2

ClinPred

0.014

GERP RS

6.2

Varity_R

0.23

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over