GeneBe

IRF6

protein-coding

interferon regulatory factor 6, the group of Interferon regulatory factors

Gene summary

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]

Previous symbols:
  • VWS
  • LPS

MANE transcript

NM_006147.4

Inheritance

AD

ClinVar variants

P:149U:122B:40

Top phenotype

Popliteal pterygium syndrome; van der Woude syndrome 1; Orofacial cleft 6

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr1:209,785,617-209,806,175

External References & Databases

Ensembl (ENSG00000117595)NCBI Gene (3664)OMIM (607199)HGNC:6121GenCCUniProt (O14896)AlphaFoldClinVar (IRF6)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~20.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant popliteal pterygium syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007334

Submitter: G2P

IRF6-related conditionDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:1040010

Submitter: Ambry Genetics

IRF6-related conditionDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:1040010

Submitter: ClinGen

IRF6 was first reported in relation to autosomal dominant IRF6-related condition in 2002 (Kondo et al., PMID: 12219090). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no differences in molecular mechanisms or inheritance pattern. Also, the phenotype appears to be a spectrum, with potential features of cleft lip/palate, lip pits, webbing of the skin, other skin anomalies, and genital anomalies. Therefore, the following disease entities have been lumped into one disease entity: Popliteal pterygium syndrome (OMIM: 119500); Van der Woude syndrome (OMIM: 119300), and Orofacial cleft (OMIM: 608864). 19 variants (missense, nonsense, frameshift) that have been reported in at least 19 probands in 9 publications (PMIDs: 12219090, 12920575, 14618417, 14757865, 18478600, 19842205, 20184620, 20803643, 33906476) are included in this curation. More evidence is available in the literature (PMIDs: 25691407, 27252970), but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse model, expression-level evidence, functional alteration data; PMIDs: 12219090, 17041601, 25784454). In summary, there is definitive evidence supporting the relationship between IRF6 and IRF6-related condition. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date 1/18/2024 (SOP Version 10).

van der Woude syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007333

Submitter: PanelApp Australia

autosomal dominant popliteal pterygium syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007334

Submitter: Orphanet

van der Woude syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007333

Submitter: Ambry Genetics

orofacial cleft 6, susceptibility toLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012141

Submitter: Labcorp Genetics (formerly Invitae)

tooth agenesisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0005486

Submitter: Orphanet

popliteal pterygium syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0017435

Submitter: Ambry Genetics

autosomal dominant popliteal pterygium syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007334

Submitter: Labcorp Genetics (formerly Invitae)

van der Woude syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007333

Submitter: Labcorp Genetics (formerly Invitae)

van der Woude syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019508

Submitter: Orphanet

van der Woude syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007333

Submitter: G2P

autosomal dominant popliteal pterygium syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007334

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Popliteal pterygium syndrome; van der Woude syndrome 1; Orofacial cleft 6AD

Manifestation: Craniofacial; Dermatologic; Genitourinary; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Variants may additionally act as susceptibility factors (rather than being involved in Mendelian-inherited dominant disease)

Refs: 13158329; 6573981; 2164325; 7628117; 10593995; 12219090; 14757865; 15317890; 16096995; 15558496; 17539900; 18247422; 18478600; 18836445; 20803643; 20799332; 21045959; 21082654; 21468557; 21739575; 21995291; 22488974; 24442519Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IRF6 variants in ClinVar

14 Conditions Cataloged
Orofacial cleft 6, susceptibility toTotal: 171
Popliteal pterygium syndromeTotal: 155
Van der Woude syndromeTotal: 152
Van der Woude syndrome 1Total: 75
not providedTotal: 75
IRF6-related conditionTotal: 57
Inborn genetic diseasesTotal: 33
not specifiedTotal: 17

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006147.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
3
clinvar
24
clinvar
3
clinvar
 31
missense
24
clinvar
47
clinvar
116
clinvar
6
clinvar
7
clinvar
 200
nonsense
26
clinvar
8
clinvar
 34
start loss
1
clinvar
1
clinvar
 2
frameshift
22
clinvar
8
clinvar
2
clinvar
 32
splice donor/acceptor (+/-2bp)
6
clinvar
5
clinvar
1
clinvar
 12
Total79701223010311

Highest pathogenic variant AF is 0.0000043368195

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_006147.4RefSeqNP_006138.17MANE Select
ENST00000367021.8EnsemblENSP00000355988.37MANE Select
NM_001206696.2RefSeqNP_001193625.16Standard
ENST00000456314.1EnsemblENSP00000403855.15Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Apoptosis
  • Primary Focal Segmental Glomerulosclerosis FSGS
  • Apoptotic Signaling Pathway
  • Hypothetical Craniofacial Development Pathway
  • the information processing pathway at the ifn beta enhancer

Biological Process

  • cell cycle arrest
  • negative regulation of cell population proliferation
  • keratinocyte differentiation
  • keratinocyte proliferation
  • positive regulation of transcription, DNA-templated

Molecular Function

  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • DNA-binding transcription activator activity, RNA polymerase II-specific
  • DNA binding
  • DNA-binding transcription factor activity
  • protein binding

Cellular Component

  • nucleus
  • cytoplasm
  • cytosol
  • cell junction
  • extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000367021
Coding exons
7
Length
20430
Individuals with no LoFs
125713
Homozygous LoFs
0
Heterozygous LoFs
1
Defined
125714
p
0.00000398
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.741382630.5240.00001433098
Missense (PolyPhen)23112.370.204681304
Synonymous1.70791010.7850.00000542883
Loss of Function4.40022.50.000.00000116238

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.00000880.0000088rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Probable DNA-binding transcriptional activator. Key determinant of the keratinocyte proliferation-differentiation switch involved in appropriate epidermal development (By similarity). Plays a role in regulating mammary epithelial cell proliferation (By similarity). May regulate WDR65 transcription (By similarity). {ECO:0000250}.;
Disease
DISEASE: Van der Woude syndrome 1 (VWS1) [MIM:119300]: An autosomal dominant developmental disorder characterized by lower lip pits, cleft lip and/or cleft palate. {ECO:0000269|PubMed:12219090, ECO:0000269|PubMed:12920575, ECO:0000269|PubMed:14618417, ECO:0000269|PubMed:14640121, ECO:0000269|PubMed:15300989, ECO:0000269|PubMed:17122170, ECO:0000269|PubMed:18478600, ECO:0000269|PubMed:19036739}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Popliteal pterygium syndrome (PPS) [MIM:119500]: An autosomal dominant disorder characterized by oro-facial, skin and genital anomalies. Expressivity is variable. Clinical features include cleft lip/palate, lower lip cysts, syngnathia, congenital ankyloblepharon filiforme in some cases, bifid scrotum, hypoplastic scrotum, hypoplastic uterus, talipes equinovarus. {ECO:0000269|PubMed:12219090, ECO:0000269|PubMed:14640121, ECO:0000269|PubMed:19036739, ECO:0000269|PubMed:20803643}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Non-syndromic orofacial cleft 6 (OFC6) [MIM:608864]: A birth defect consisting of cleft lips with or without cleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides and range in severity from a simple notch in the upper lip to a complete opening in the lip extending into the floor of the nostril and involving the upper gum. {ECO:0000269|PubMed:15317890, ECO:0000269|PubMed:21082654}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.413

Intolerance Scores

LoFtool
0.0332
RVIS EVS
-0.18
RVIS percentile EVS
39.95

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.978

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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