IRF3
protein-codinginterferon regulatory factor 3, the group of Interferon regulatory factors
Gene summary
This gene encodes a member of the interferon regulatory transcription factor (IRF) family. The encoded protein is found in an inactive cytoplasmic form that upon serine/threonine phosphorylation forms a complex with CREBBP. This complex translocates to the nucleus and activates the transcription of interferons alpha and beta, as well as other interferon-induced genes. The protein plays an important role in the innate immune response against DNA and RNA viruses. Mutations in this gene are associated with Encephalopathy, acute, infection-induced, herpes-specific, 7. [provided by RefSeq, Sep 2020]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014680
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: Individuals may be susceptible to severe herpes simplex virus infections includingherpes encephalitis has been described, and awareness may allow early diagnosis and treatment, potentially decreasing morbidity and mortality
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to IRF3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001571.6. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 6 | 19 | 1 | 26 | ||
| missense | 61 | 18 | 1 | 80 | ||
| nonsense | 3 | 3 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 71 | 37 | 2 | 110 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001562.1 | 7 | MANE Select | |
| Ensembl | ENSP00000366344.3 | 7 | MANE Select | |
| RefSeq | NP_001184051.1 | 7 | Standard | |
| RefSeq | NP_001184052.1 | 7 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
- Pertussis - Homo sapiens (human)
- Influenza A - Homo sapiens (human)
- Cytosolic DNA-sensing pathway - Homo sapiens (human)
- Toll-like receptor signaling pathway - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- transcription by RNA polymerase II
- apoptotic process
- cellular response to DNA damage stimulus
- viral process
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription repressor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- DNA binding
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000601291
- Coding exons
- 7
- Length
- 6307
- Individuals with no LoFs
- 125727
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 20
- Defined
- 125747
- p
- 0.0000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.08 | 212 | 261 | 0.812 | 0.0000149 | 2849 |
| Missense (PolyPhen) | 60 | 84.865 | 0.707 | 885 | ||
| Synonymous | -0.918 | 125 | 113 | 1.11 | 0.00000678 | 974 |
| Loss of Function | 1.82 | 9 | 17.1 | 0.526 | 7.34e-7 | 186 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00012 | 0.00012 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Key transcriptional regulator of type I interferon (IFN)-dependent immune responses which plays a critical role in the innate immune response against DNA and RNA viruses. Regulates the transcription of type I IFN genes (IFN-alpha and IFN-beta) and IFN-stimulated genes (ISG) by binding to an interferon-stimulated response element (ISRE) in their promoters. Acts as a more potent activator of the IFN-beta (IFNB) gene than the IFN-alpha (IFNA) gene and plays a critical role in both the early and late phases of the IFNA/B gene induction. Found in an inactive form in the cytoplasm of uninfected cells and following viral infection, double-stranded RNA (dsRNA), or toll-like receptor (TLR) signaling, is phosphorylated by IKBKE and TBK1 kinases. This induces a conformational change, leading to its dimerization and nuclear localization and association with CREB binding protein (CREBBP) to form dsRNA-activated factor 1 (DRAF1), a complex which activates the transcription of the type I IFN and ISG genes. Can activate distinct gene expression programs in macrophages and can induce significant apoptosis in primary macrophages.;
- Disease
- DISEASE: Encephalopathy, acute, infection-induced, Herpes- specific, 7 (IIAE7) [MIM:616532]: A rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. It is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. {ECO:0000269|PubMed:26216125}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.339
Intolerance Scores
- LoFtool
- 0.228
- RVIS EVS
- 0.51
- RVIS percentile EVS
- 80.2
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |