IRF3

interferon regulatory factor 3, the group of Interferon regulatory factors

Basic information

Region (hg38): 19:49659568-49665875

Links

ENSG00000126456 ∙ NCBI:3661 ∙ OMIM:603734 ∙ HGNC:6118 ∙ Uniprot:Q14653 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Encephalopathy, acute, infection-induceed (herpes-specific), susceptibility to, 7	AD	Allergy/Immunology/Infectious	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	Allergy/Immunology/Infectious	26216125

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the IRF3 gene.

• Inborn genetic diseases (28 variants)
• not provided (6 variants)
• not specified (5 variants)
• Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 7 (2 variants)
• IRF3-related condition (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the IRF3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				1		1
missense			29	5	2	36
nonsense			1			1
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			1		1	2
Total	0	0	31	6	3

Variants in IRF3

This is a list of pathogenic ClinVar variants found in the IRF3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
19-49659612-C-T		not specified	Uncertain significance (Apr 12, 2022)
19-49659618-G-C		not specified	Uncertain significance (Mar 21, 2023)
19-49659652-C-G		not specified	Benign (Jan 24, 2024)
19-49659656-C-T		not specified	Uncertain significance (Apr 25, 2022)
19-49659717-G-A		IRF3-related disorder	Likely benign (Oct 18, 2023)
19-49659723-G-A		IRF3-related disorder	Benign (Jan 29, 2024)
19-49659731-G-C		not specified	Uncertain significance (Jun 09, 2022)
19-49659751-T-C		not specified	Likely benign (Jun 23, 2023)
19-49659787-C-T		not specified	Likely benign (May 23, 2023)
19-49659795-G-C		not specified	Uncertain significance (Feb 12, 2024)
19-49660724-C-A		not specified	Uncertain significance (Aug 11, 2022)
19-49660741-G-A		Multisystem inflammatory syndrome in children	risk factor (Nov 14, 2021)
19-49660745-G-A		IRF3-related disorder	Uncertain significance (Oct 26, 2022)
19-49660748-C-T		not specified	Uncertain significance (Apr 17, 2023)
19-49660795-G-A		not specified	Likely benign (Dec 19, 2023)
19-49660807-C-T		not specified	Uncertain significance (Jul 26, 2023)
19-49661959-G-A		not specified	Uncertain significance (Dec 27, 2023)
19-49661965-A-G		not specified	Uncertain significance (Sep 14, 2022)
19-49661967-G-C		not specified	Uncertain significance (Dec 20, 2022)
19-49661985-C-G		not specified	Uncertain significance (Mar 29, 2023)
19-49662015-A-C		not specified	Uncertain significance (May 24, 2023)
19-49662045-C-T		IRF3-related disorder	Likely benign (Sep 17, 2019)
19-49662076-C-T		Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 7	risk factor (Aug 24, 2015)
19-49662096-C-T		IRF3-related disorder	Likely benign (Jun 05, 2019)
19-49662101-C-T		Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 7 • IRF3-related disorder	Likely benign (Mar 01, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
IRF3	protein_coding	protein_coding	ENST00000601291	7	6307

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000116	0.956	125727	0	20	125747	0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.08	212	261	0.812	0.0000149	2849
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000579	0.0000579
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.000124	0.000123
Middle Eastern	0.0000544	0.0000544
South Asian	0.00	0.00
Other	0.000490	0.000489

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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);NOD-like receptor signaling pathway - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Hepatitis C - Homo sapiens (human);Hepatitis B - Homo sapiens (human);Measles - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);RIG-I-like receptor signaling pathway - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);Regulation of toll-like receptor signaling pathway;White fat cell differentiation;Apoptosis;Apoptotic Signaling Pathway;TLR4 Signaling and Tolerance;Toll-like Receptor Signaling;RIG-I-like Receptor Signaling;Fibrin Complement Receptor 3 Signaling Pathway;White fat cell differentiation;Ebola Virus Pathway on Host;Ebola Virus Pathway on Host;Toll-like Receptor Signaling Pathway;the information processing pathway at the ifn beta enhancer;Cytokine Signaling in Immune system;TICAM1-dependent activation of IRF3/IRF7;Toll Like Receptor 3 (TLR3) Cascade;IRF3 mediated activation of type 1 IFN;ZBP1(DAI) mediated induction of type I IFNs;Toll-Like Receptors Cascades;TRAF6 mediated IRF7 activation;DDX58/IFIH1-mediated induction of interferon-alpha/beta;STING mediated induction of host immune responses;LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production;Regulation of innate immune responses to cytosolic DNA;Innate Immune System;Immune System;IRF3-mediated induction of type I IFN;TRAF3-dependent IRF activation pathway;Negative regulators of DDX58/IFIH1 signaling;Interferon gamma signaling;Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon;Cytosolic sensors of pathogen-associated DNA ;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade;Interferon alpha/beta signaling;ISG15 antiviral mechanism;Antiviral mechanism by IFN-stimulated genes;Interferon Signaling (Consensus)

Recessive Scores

• pRec: 0.339

Intolerance Scores

• loftool: 0.228
• rvis_EVS: 0.51
• rvis_percentile_EVS: 80.2

Haploinsufficiency Scores

• pHI: 0.145
• hipred: Y
• hipred_score: 0.627
• ghis: 0.466

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Irf3
• Phenotype: immune system phenotype; homeostasis/metabolism phenotype; cellular phenotype

Gene ontology

• 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;lipopolysaccharide-mediated signaling pathway;regulation of type I interferon production;negative regulation of type I interferon production;positive regulation of type I interferon production;positive regulation of interferon-alpha production;positive regulation of interferon-beta production;TRIF-dependent toll-like receptor signaling pathway;MDA-5 signaling pathway;positive regulation of I-kappaB kinase/NF-kappaB signaling;type I interferon biosynthetic process;positive regulation of transcription by RNA polymerase II;positive regulation of cytokine secretion;regulation of inflammatory response;defense response to virus;interferon-gamma-mediated signaling pathway;type I interferon signaling pathway;positive regulation of type I interferon-mediated signaling pathway;cellular response to exogenous dsRNA;macrophage apoptotic process;programmed necrotic cell death
• Cellular component: nucleus;nucleoplasm;cytoplasm;cytosol
• 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;transcription coregulator activity;protein binding;protein domain specific binding;identical protein binding;protein homodimerization activity;sequence-specific DNA binding