IRF9

protein-coding

interferon regulatory factor 9, the group of Interferon regulatory factors

Gene summary

This gene encodes a member of the interferon regulatory factor (IRF) family, a group of transcription factors with diverse roles, including virus-mediated activation of interferon, and modulation of cell growth, differentiation, apoptosis, and immune system activity. Members of the IRF family are characterized by a conserved N-terminal DNA-binding domain containing tryptophan (W) repeats. Mutations in this gene result in Immunodeficiency 65. [provided by RefSeq, Jul 2020]

Previous symbols:

ISGF3G

MANE transcript

NM_006084.5

Inheritance

ClinVar variants

U:132B:75

Top phenotype

Immunodeficiency 65

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr14:24,161,234-24,168,043

External References & Databases

Ensembl (ENSG00000213928)

Transcript & Mutation Effects

hg38 • Region Span ~6.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 65, susceptibility to viral infectionsMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032848

Submitter: PanelApp Australia

immunodeficiency 65, susceptibility to viral infectionsMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032848

Submitter: ClinGen

*IRF9* was first reported in relation to Autosomal Recessive susceptibility to viral infection in 2018 (PMID:30143481). At least 2 unique variants (missense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Experimental evidence incldues evidence of functional alteration (PMID 35182547, 30143481 and 30826365), rescue model (PMID 30143481 and 30826365), cell culture model (PMID 30826365), and mouse model (PMID 22496215). Variants in this gene have been reported in at least 2 probands in 2 publications (PMID 30143481 and 30826365). Variants in this gene segregated with disease in 1 additional family member. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

immunodeficiency 65, susceptibility to viral infectionsLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0032848

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Immunodeficiency 65AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals have been described with early-onset severe and recurrent viral infections, and antiinfectious prophylaxis (intravenous immunoglobulin has been described) and early and aggressive treatment of infections may be beneficial; live attenuated vaccines have been reported as resulting in poor outcomes in patients with impaired interferon responses

Refs: 30143481; 30826365

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IRF9 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 240

not specifiedTotal: 54

Immunodeficiency 65, susceptibility to viral infectionsTotal: 5

IRF9-related disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006084.5. 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			1 clinvar	64 clinvar	2 clinvar	67
missense			123 clinvar	9 clinvar		132
nonsense			1 clinvar			1
start loss						0
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	132	73	2	207

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 96 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006084.5	RefSeq	NP_006075.3	8	MANE Select
ENST00000396864.8	Ensembl	ENSP00000380073.3	8	MANE Select
NM_001385400.1	RefSeq	NP_001372329.1	9	Standard
NM_001385401.1	RefSeq	NP_001372330.1	8	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)
Jak-STAT signaling pathway - Homo sapiens (human)
Influenza A - Homo sapiens (human)
Necroptosis - Homo sapiens (human)
NOD-like receptor signaling pathway - Homo sapiens (human)

Biological Process

regulation of transcription by RNA polymerase II
transcription by RNA polymerase II
cell surface receptor signaling pathway
defense response to virus
interferon-gamma-mediated signaling pathway

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription factor activity
protein binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396864
Coding exons: 8
Length: 5513
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125744
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.57	161	228	0.707	0.0000128	2551
Missense (PolyPhen)		48	93.605	0.51279		1036
Synonymous	1.26	73	88.0	0.830	0.00000483	778
Loss of Function	3.36	4	20.4	0.196	0.00000113	204

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	0.000061	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000045	0.000044	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor that mediates signaling by type I IFNs (IFN-alpha and IFN-beta). Following type I IFN binding to cell surface receptors, Jak kinases (TYK2 and JAK1) are activated, leading to tyrosine phosphorylation of STAT1 and STAT2. IRF9/ISGF3G associates with the phosphorylated STAT1:STAT2 dimer to form a complex termed ISGF3 transcription factor, that enters the nucleus. ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of interferon stimulated genes, which drive the cell in an antiviral state.;

Intolerance Scores

LoFtool: 0.147
RVIS EVS: -0.16
RVIS percentile EVS: 41.91

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.861

Gene Damage Prediction

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