IRF8

protein-coding

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

Gene summary

Interferon consensus sequence-binding protein (ICSBP) is a transcription factor of the interferon (IFN) regulatory factor (IRF) family. Proteins of this family are composed of a conserved DNA-binding domain in the N-terminal region and a divergent C-terminal region that serves as the regulatory domain. The IRF family proteins bind to the IFN-stimulated response element (ISRE) and regulate expression of genes stimulated by type I IFNs, namely IFN-alpha and IFN-beta. IRF family proteins also control expression of IFN-alpha and IFN-beta-regulated genes that are induced by viral infection. [provided by RefSeq, Jul 2008]

Previous symbols:

ICSBP1

MANE transcript

NM_002163.4

Inheritance

AD, AR

ClinVar variants

P:4U:217B:142

Top phenotype

Immunodeficiency 32A; Immunodeficiency 32B

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr16:85,899,116-85,922,606

External References & Databases

Ensembl (ENSG00000140968)

Transcript & Mutation Effects

hg38 • Region Span ~23.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiencySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013957

Submitter: Illumina

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiencySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013957

Submitter: Orphanet

immunodeficiency 32BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009194

Submitter: PanelApp Australia

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiencySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013957

Submitter: PanelApp Australia

immunodeficiency 32BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009194

Submitter: Labcorp Genetics (formerly Invitae)

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiencyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013957

Submitter: Ambry Genetics

immunodeficiency 32BMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009194

Submitter: Ambry Genetics

immunodeficiency 32BMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009194

Submitter: Ambry Genetics

immunodeficiency 32BMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009194

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiencySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013957

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Immunodeficiency 32A; Immunodeficiency 32BAD

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: 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

Refs: 21524210

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IRF8 variants in ClinVar

9 Conditions Cataloged

Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiencyTotal: 398

Immunodeficiency 32BTotal: 398

not specifiedTotal: 58

not providedTotal: 51

Inborn genetic diseasesTotal: 35

IRF8-related disorderTotal: 19

Inherited Immunodeficiency DiseasesTotal: 1

Esophageal atresia/tracheoesophageal fistulaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002163.4. 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			7 clinvar	124 clinvar	7 clinvar	138
missense	1 clinvar	2 clinvar	199 clinvar	11 clinvar		213
nonsense			3 clinvar			3
start loss						0
frameshift		1 clinvar	7 clinvar			8
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	3	217	135	7	363

Highest pathogenic variant AF is 0.0000065674544

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002163.4	RefSeq	NP_002154.1	8	MANE Select
ENST00000268638.10	Ensembl	ENSP00000268638.4	8	MANE Select
NM_001363907.1	RefSeq	NP_001350836.1	9	Standard
NM_001363908.1	RefSeq	NP_001350837.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
irf8	Danio rerio	Structure: neutrophil Quality: increased amount abnormal

Gene / Model

Organism

Observed Phenotype

irf8

Danio rerio

Structure: neutrophil

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

negative regulation of transcription by RNA polymerase II
phagocytosis
autophagy
immune response
myeloid cell differentiation

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

Cellular Component

nucleus
nucleoplasm
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000268638
Coding exons: 8
Length: 23807
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125745
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.19	220	275	0.799	0.0000199	2775
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000056	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.449

Intolerance Scores

LoFtool: 0.174
RVIS EVS: -0.18
RVIS percentile EVS: 40.45

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.991

Gene Damage Prediction

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