IRAK4

protein-coding

interleukin 1 receptor associated kinase 4

Gene summary

This gene encodes a kinase that activates NF-kappaB in both the Toll-like receptor (TLR) and T-cell receptor (TCR) signaling pathways. The protein is essential for most innate immune responses. Mutations in this gene result in IRAK4 deficiency and recurrent invasive pneumococcal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

MANE transcript

NM_016123.4

Inheritance

ClinVar variants

P:38U:142B:67

Top phenotype

Immunodeficiency 67

gnomAD constraint

pLI —, LoF o/e 0.69

Max pathogenic AF

—

Genomic locus

chr12:43,758,944-43,798,307

External References & Databases

Ensembl (ENSG00000198001)

Transcript & Mutation Effects

hg38 • Region Span ~39.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 67STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011888

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency 67STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011888

Submitter: PanelApp Australia

immunodeficiency 67SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011888

Submitter: Orphanet

Clinical Genomic Database (CGD)

Immunodeficiency 67AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial

Refs: 12637671; 15069404; 16647421; 17893200; 21734245; 26825884

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IRAK4 variants in ClinVar

9 Conditions Cataloged

Immunodeficiency 67Total: 259

Inborn genetic diseasesTotal: 44

not providedTotal: 36

not specifiedTotal: 16

IRAK4-related disorderTotal: 5

IRAK4-related disordersTotal: 4

Congenital dyserythropoietic anemiaTotal: 2

Primary ciliary dyskinesiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016123.4. 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 clinvar	60 clinvar		63
missense		1 clinvar	137 clinvar	6 clinvar	1 clinvar	145
nonsense	10 clinvar	2 clinvar				12
start loss						0
frameshift	13 clinvar	6 clinvar				19
splice donor/acceptor (+/-2bp)	1 clinvar	5 clinvar	2 clinvar			8
Total	24	14	142	66	1	247

Highest pathogenic variant AF is 0.00064218225

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016123.4	RefSeq	NP_057207.2	11	MANE Select
ENST00000613694.5	Ensembl	ENSP00000479889.3	11	MANE Select
NM_001114182.3	RefSeq	NP_001107654.1	11	Standard
NM_001145256.2	RefSeq	NP_001138728.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pertussis - Homo sapiens (human)
Neurotrophin signaling pathway - Homo sapiens (human)
Influenza A - Homo sapiens (human)
Chagas disease (American trypanosomiasis) - Homo sapiens (human)
Toll-like receptor signaling pathway - Homo sapiens (human)

Biological Process

cytokine production
toll-like receptor signaling pathway
neutrophil mediated immunity
MyD88-dependent toll-like receptor signaling pathway
JNK cascade

Molecular Function

magnesium ion binding
protein kinase activity
protein serine/threonine kinase activity
interleukin-1 receptor binding
protein binding

Cellular Component

extracellular space
nucleus
cytoplasm
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000448290
Coding exons: 11
Length: 30600
Individuals with no LoFs: 125656
Homozygous LoFs: 0
Heterozygous LoFs: 91
Defined: 125747
p: 0.000362

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.216	228	237	0.961	0.0000111	3050
Missense (PolyPhen)		72	87.971	0.81845		1079
Synonymous	0.600	71	77.7	0.913	0.00000352	841
Loss of Function	1.37	16	23.1	0.693	0.00000117	294

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00044	0.00044	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00058	0.00058	rare
South Asian	0.00013	0.00013	rare
Other	0.00066	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways (PubMed:17878374). Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino- mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA- IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections. {ECO:0000269|PubMed:11960013, ECO:0000269|PubMed:12538665, ECO:0000269|PubMed:15084582, ECO:0000269|PubMed:17217339, ECO:0000269|PubMed:17337443, ECO:0000269|PubMed:17878374, ECO:0000269|PubMed:17997719, ECO:0000269|PubMed:20400509, ECO:0000269|PubMed:24316379}.;
Disease: DISEASE: Recurrent isolated invasive pneumococcal disease 1 (IPD1) [MIM:610799]: Recurrent invasive pneumococcal disease (IPD) is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD. {ECO:0000269|PubMed:16950813}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: IRAK4 deficiency (IRAK4D) [MIM:607676]: Causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children. {ECO:0000269|PubMed:12637671, ECO:0000269|PubMed:12925671, ECO:0000269|PubMed:17878374, ECO:0000269|PubMed:19663824, ECO:0000269|PubMed:21057262, ECO:0000269|PubMed:24316379}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.302

Intolerance Scores

LoFtool: 0.284
RVIS EVS: -0.25
RVIS percentile EVS: 35.99

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.396

Gene Damage Prediction

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