IRF4
protein-codinginterferon regulatory factor 4, the group of Interferon regulatory factors
Gene summary
The protein encoded by this gene belongs to the IRF (interferon regulatory factor) family of transcription factors, characterized by an unique tryptophan pentad repeat DNA-binding domain. The IRFs are important in the regulation of interferons in response to infection by virus, and in the regulation of interferon-inducible genes. This family member is lymphocyte specific and negatively regulates Toll-like-receptor (TLR) signaling that is central to the activation of innate and adaptive immune systems. A chromosomal translocation involving this gene and the IgH locus, t(6;14)(p25;q32), may be a cause of multiple myeloma. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2010]
- MUM1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~19.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0015131
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0015131
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0015131
Submitter: ClinGen
The IRF4 gene encodes the transcription factor interferon regulatory factor 4. IRF4 is a member of the human interferon (IFN) regulatory factor (IRF) family. IRF4 can function either as an activating or an inhibitory transcription factor depending on its transcription cofactors as a transcription factor, it can bind to the canonical IFN-stimulated response elements (ISREs) as a homodimer; and/or to erythroblast transformation-specific IRF composite elements (EICEs) and activating protein 1 (AP1)–IRF composite elements (AICE1 or AICE2) as a heterodimer requiring PU.1 or SPIB, or AP-1 family members. It is a predominantly hematopoietic TF that is necessary for B and T cell development, differentiation and function, as well as dendritic cells and macrophages. It plays an essential role in IgM, IgG, and IgA secretion, antibody responses, the generation of germinal center B cells, and is required for Ig class-switch recombination and plasma cell differentiation. IRF4 Autosomal Dominant primary immunodeficiency (MONDO: N/A) has a wide range of phenotypes: combined immunodeficiency, age of onset early childhood, recurrent respiratory infections/pneumonia, recurrent viral infections/opportunistic pathogens, recurrent diarrhea, decreased circulating antibody levels and abnormal B/T cell subset distribution. A total of four variants, including nonsense and missense, have been reported in 15 patients in 4 publications only (PMID: 36662884, 36917008, 29537367, 29408330). The missense variants, but not the non-sense variant, were found in an autosomal dominant trait, and the disease mechanism is suggested to be loss of function. Only one patient has a bi-allelic genetic condition associated with IRF4 deficiency, the genetic mechanism underlying the defect consisted of a maternal uniparental isodisomy (UPID). This patient was recorded but not scored. Experimental evidence includes: impaired maturation, decreased immunoglobulin isotype switching, and defective plasma cell differentiation in patient B cells, whereas their T cells contained reduced TH17 and TFH populations and exhibited decreased cytokine production, gain-of-function hypermorph activity by binding to DNA with higher affinity than IRF4WT. Despite this increased affinity for DNA, the transcriptional activity on IRF4 canonical genes was reduced, indicating hypomorphic activity, and neomorphic function by binding to noncanonical DNA sites to alter the gene expression profile. Additionally, the IRF4 knockout mouse recapitulates most of the cellular phenotypes, and results in the impairment of mature B and T lymphocytes. In summary, there is strong evidence to support this gene-disease relationship. Clinical data included in the curation span the time period from 2018 until present, therefore the classification is definitive.
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Dermatologic
Intervention: Allergy/Immunology/Infectious
Rationale: The condition involves immunodeficiency, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to IRF4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002460.4. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 3 | 105 | 3 | 111 | ||
| missense | 3 | 134 | 24 | 4 | 165 | |
| nonsense | 2 | 2 | ||||
| start loss | 2 | 2 | ||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 5 | 5 | ||||
| Total | 3 | 0 | 146 | 131 | 7 | 287 |
Highest pathogenic variant AF is 6.840778e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002451.2 | 8 | MANE Select | |
| Ensembl | ENSP00000370343.4 | 8 | MANE Select | |
| RefSeq | NP_001182215.1 | 8 | Standard | |
| Ensembl | ENSP00000436094.2 | 8 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| irf4a | Danio rerio | Structure: thymus Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Th17 cell differentiation - Homo sapiens (human)
- White fat cell differentiation
- B Cell Receptor Signaling Pathway
- Apoptosis
- Vitamin D Receptor Pathway
Biological Process
- peptidyl-lysine methylation
- cytokine-mediated signaling pathway
- negative regulation of toll-like receptor signaling pathway
- T cell activation
- defense response to protozoan
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- DNA-binding transcription factor activity
- protein binding
Cellular Component
- nuclear nucleosome
- nucleus
- nucleoplasm
- cytosol
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000380956
- Coding exons
- 8
- Length
- 19709
- Individuals with no LoFs
- 125730
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 18
- Defined
- 125748
- p
- 0.0000716
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.85 | 144 | 278 | 0.518 | 0.0000164 | 2960 |
| Missense (PolyPhen) | 33 | 101.58 | 0.32488 | 1106 | ||
| Synonymous | 0.309 | 115 | 119 | 0.964 | 0.00000813 | 845 |
| Loss of Function | 3.78 | 4 | 24.0 | 0.167 | 0.00000130 | 248 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00012 | rare |
| Latino/Admixed American | 0.000033 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00059 | 0.00054 | rare |
| Finnish | 0.000047 | 0.000046 | rare |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0.000037 | 0.000033 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcriptional activator. Binds to the interferon- stimulated response element (ISRE) of the MHC class I promoter. Binds the immunoglobulin lambda light chain enhancer, together with PU.1. Probably plays a role in ISRE-targeted signal transduction mechanisms specific to lymphoid cells. Involved in CD8(+) dendritic cell differentiation by forming a complex with the BATF-JUNB heterodimer in immune cells, leading to recognition of AICE sequence (5'-TGAnTCA/GAAA-3'), an immune-specific regulatory element, followed by cooperative binding of BATF and IRF4 and activation of genes (By similarity). {ECO:0000250|UniProtKB:Q64287}.;
- Disease
- DISEASE: Multiple myeloma (MM) [MIM:254500]: A malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. {ECO:0000269|PubMed:9326949}. Note=The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving IRF4 has been found in multiple myeloma. Translocation t(6;14)(p25;q32) with the IgH locus.;
Recessive Scores
- pRec
- 0.304
Intolerance Scores
- LoFtool
- 0.136
- RVIS EVS
- -0.6
- RVIS percentile EVS
- 17.91
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 |