IRF8

interferon regulatory factor 8, the group of Interferon regulatory factors |MicroRNA protein coding host genes

Basic information

Region (hg38): 16:85899116-85922606

Previous symbols: [ "ICSBP1" ]

Links

ENSG00000140968 ∙ NCBI:3394 ∙ OMIM:601565 ∙ HGNC:5358 ∙ Uniprot:Q02556 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency (Supportive), mode of inheritance: AD
• immunodeficiency 32B (Moderate), mode of inheritance: AR
• Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency (Strong), mode of inheritance: AD
• Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency (Strong), mode of inheritance: AD
• immunodeficiency 32B (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 32A; Immunodeficiency 32B	AD	Allergy/Immunology/Infectious	Individuals with Immunodeficiency 32A (CD11C-positive/CD1C-positive dendritic cell deficiency) have been described as demonstrating disseminated BCG disease that was amenable to treatment, and preventive measures, as well as prompt treatment of infection, may be beneficial; Individuals with Immunodeficiency 32B (monocyte and dendritic cell deficiency) demonstrate immunodeficiency, with severe opportunistic infections, and prophylactic measures and prompt and aggressive treatment of infections may be beneficial; HSCT has been described	Allergy/Immunology/Infectious	21524210

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the IRF8 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the IRF8 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			2	99	11	112
missense			149	8		157
nonsense						0
start loss						0
frameshift			5			5
inframe indel			1			1
splice donor/acceptor (+/-2bp)			1			1
splice region			11	15		26
non coding			1	28	11	40
Total	0	0	159	135	22

Variants in IRF8

This is a list of pathogenic ClinVar variants found in the IRF8 region.

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

Position	Type	Phenotype	Significance	ClinVar
16-85899201-AGACGGCGGCAG-A		Immunodeficiency 32B	Uncertain significance (-)
16-85902776-G-GGGCTGCTGGT		not specified	Benign (Jan 24, 2024)
16-85902783-T-A		not specified	Benign (Jan 24, 2024)
16-85902783-T-TGGTGGCTGCA		not specified	Benign (Jan 24, 2024)
16-85902786-T-TGGCTGCAGGG		not specified	Benign (Jan 24, 2024)
16-85902786-T-TGGCTGCAGGC		not specified	Benign (Jan 24, 2024)
16-85902796-T-TGGCTGCAGGA		not specified	Benign (Jan 24, 2024)
16-85903021-T-C		Immunodeficiency 32B;Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency • IRF8-related disorder	Likely benign (Dec 15, 2023)
16-85903024-C-G			Uncertain significance (May 15, 2018)
16-85903025-C-T			Uncertain significance (Jan 31, 2017)
16-85903029-ATGG-A		Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency;Immunodeficiency 32B	Uncertain significance (Feb 27, 2022)
16-85903034-G-A		Immunodeficiency 32B;Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency	Uncertain significance (Jul 25, 2023)
16-85903037-C-T		Immunodeficiency 32B;Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency	Uncertain significance (Aug 17, 2021)
16-85903040-C-T		Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency;Immunodeficiency 32B	Uncertain significance (May 03, 2020)
16-85903050-A-T		Immunodeficiency 32B;Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency	Uncertain significance (May 18, 2023)
16-85903051-G-A		Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency;Immunodeficiency 32B	Likely benign (May 08, 2022)
16-85903060-C-G		Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency;Immunodeficiency 32B	Uncertain significance (Sep 15, 2021)
16-85903060-C-T		Immunodeficiency 32B;Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency	Likely benign (Aug 24, 2023)
16-85903061-G-A		Immunodeficiency 32B;Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency	Uncertain significance (Jul 17, 2023)
16-85903068-T-C			Uncertain significance (Aug 01, 2024)
16-85903071-A-G		Immunodeficiency 32B;Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency	Uncertain significance (Dec 30, 2022)
16-85903073-A-G		Immunodeficiency 32B;Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency	Uncertain significance (Oct 20, 2022)
16-85903074-G-A		Immunodeficiency 32B;Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency	Uncertain significance (May 18, 2023)
16-85903082-T-C		Neoplasm	- (-)
16-85903083-A-G		Immunodeficiency 32B;Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency	Uncertain significance (Oct 18, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
IRF8	protein_coding	protein_coding	ENST00000268638	8	23807

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.948	0.0519	125740	0	5	125745	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.19	220	275	0.799	0.0000199	2775
Missense in Polyphen		70	133.74	0.5234		1352
Synonymous	-1.67	135	112	1.20	0.00000823	814
Loss of Function	3.81	3	22.5	0.133	0.00000121	230

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000564	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000264	0.0000264
Middle Eastern	0.0000564	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Plays a role as a transcriptional activator or repressor (PubMed:25122610). Specifically binds to the upstream regulatory region of type I IFN and IFN-inducible MHC class I genes (the interferon consensus sequence (ICS)). Plays a negative regulatory role in cells of the immune system. 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 IRF8 and activation of genes (By similarity). Positively regulates macroautophagy in dendritic cells (PubMed:29434592). {ECO:0000250|UniProtKB:P23611, ECO:0000269|PubMed:25122610, ECO:0000269|PubMed:29434592}.
• Disease: DISEASE: Immunodeficiency 32A (IMD32A) [MIM:614893]: An immunologic disorder characterized by abnormal peripheral blood myeloid phenotype with a marked loss of CD11C-positive/CD1C dendritic cells, resulting in selective susceptibility to mycobacterial infections. {ECO:0000269|PubMed:21524210}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Immunodeficiency 32B (IMD32B) [MIM:226990]: An autosomal recessive primary immunodeficiency characterized by monocyte and dendritic cell deficiency, myeloproliferation, and susceptibility to severe opportunistic infections, including disseminated BCG infection and oral candidiasis. {ECO:0000269|PubMed:21524210, ECO:0000269|PubMed:25122610}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Pertussis - Homo sapiens (human);Vitamin D Receptor Pathway;Development of pulmonary dendritic cells and macrophage subsets;Type II interferon signaling (IFNG);Cytokine Signaling in Immune system;Immune System;Interferon gamma signaling;Interferon alpha/beta signaling;GMCSF-mediated signaling events;Validated targets of C-MYC transcriptional repression;Interferon Signaling (Consensus)

Recessive Scores

• pRec: 0.449

Intolerance Scores

• loftool: 0.174
• rvis_EVS: -0.18
• rvis_percentile_EVS: 40.45

Haploinsufficiency Scores

• pHI: 0.111
• hipred: Y
• hipred_score: 0.851
• ghis: 0.542

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.991

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Irf8
• Phenotype: homeostasis/metabolism phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); hematopoietic system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); neoplasm; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); immune system phenotype

Zebrafish Information Network

• Gene name: irf8
• Affected structure: neutrophil
• Phenotype tag: abnormal
• Phenotype quality: increased amount

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;phagocytosis;autophagy;immune response;myeloid cell differentiation;positive regulation of interferon-gamma production;positive regulation of interleukin-12 production;defense response to bacterium;defense response to protozoan;negative regulation of growth of symbiont in host;positive regulation of transcription by RNA polymerase II;interferon-gamma-mediated signaling pathway;type I interferon signaling pathway;cellular response to lipopolysaccharide;cellular response to interferon-gamma
• 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;protein binding