rs200166664

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PM5PP2PP3_Moderate

The NM_006147.4(IRF6):c.1199G>T(p.Arg400Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R400Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IRF6
NM_006147.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.32

Publications

11 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: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-209788625-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 101515.Status of the report is no_assertion_criteria_provided, 0 stars.

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 van der Woude syndrome 1, van der Woude syndrome, autosomal dominant popliteal pterygium syndrome, orofacial cleft 6, susceptibility to, tooth agenesis, IRF6-related condition, popliteal pterygium syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF6	NM_006147.4 link	c.1199G>T	p.Arg400Leu	missense_variant	Exon 9 of 9	ENST00000367021.8	NP_006138.1
IRF6	NM_001206696.2 link	c.914G>T	p.Arg305Leu	missense_variant	Exon 7 of 7		NP_001193625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF6	ENST00000367021.8 link	c.1199G>T	p.Arg400Leu	missense_variant	Exon 9 of 9	1	NM_006147.4	ENSP00000355988.3
ENSG00000289700	ENST00000696133.1 link	c.1199G>T	p.Arg400Leu	missense_variant	Exon 9 of 10			ENSP00000512426.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000511

AC:

AN:

195770

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1432300

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710526

African (AFR)

AF:

0.00

AC:

AN:

32578

American (AMR)

AF:

0.00

AC:

AN:

39794

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25300

East Asian (EAS)

AF:

0.00

AC:

AN:

37838

South Asian (SAS)

AF:

0.00

AC:

AN:

82916

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5534

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101102

Other (OTH)

AF:

0.00

AC:

AN:

59426

GnomAD4 genome

Cov.:

ExAC

AF:

0.000151

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

.;D

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

2.9

.;M

PhyloP100

7.3

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.59

MutPred

0.86

.;Gain of catalytic residue at V398 (P = 0.0945);

MVP

0.99

MPC

1.8

ClinPred

1.0

GERP RS

5.7

Varity_R

0.85

gMVP

0.87

Mutation Taster

=12/88

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over