JAK3

protein-coding

Janus kinase 3, the group of Jak family tyrosine kinases

Gene summary

The protein encoded by this gene is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction. It is predominantly expressed in immune cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors. Mutations in this gene are associated with autosomal SCID (severe combined immunodeficiency disease). [provided by RefSeq, Jul 2008]

MANE transcript

NM_000215.4

Inheritance

ClinVar variants

P:136U:345B:448

Top phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, natural killer cell-negative

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr19:17,824,780-17,848,071

External References & Databases

Ensembl (ENSG00000105639)

Transcript & Mutation Effects

hg38 • Region Span ~23.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

T-B+ severe combined immunodeficiency due to JAK3 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010938

Submitter: Labcorp Genetics (formerly Invitae)

T-B+ severe combined immunodeficiency due to JAK3 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010938

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.

T-B+ severe combined immunodeficiency due to JAK3 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010938

Submitter: Orphanet

T-B+ severe combined immunodeficiency due to JAK3 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010938

Submitter: ClinGen

JAK3 - SCID, autosomal recessive, T-negative/B-positive type Phenotype MIM:600802 JAK3 was first reported in relation to autosomal recessive severe combined immune deficiency (T-negative/B-positive type) in 1994 (Russell et al., PMID:7973658). At least 27 unique variants (missense, in-frame indel, nonsense, frameshift, large deletion, splice) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 15 probands, in at least 6 publications (PMID:9354668, PMID:7659163, PMID: 7481768, PMID: 30032486, PMID: 14615376, PMID: 9753072). Probands described range in age of onset between approximately 3 and 14 months. Common phenotypes include recurrent upper and lower respiratory tract infections, decreased circulating antibody levels, recurrent diarrhea, lack of circulating T cells, and a normal number of B lymphocytes. This gene-disease association is supported by mice models, cell culture models, expression studies, and in vitro functional assays (PMID: 28513593, PMID: 14615376, PMID: 10075926, PMID: 7481768). Protein encoded by JAK3 is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction. It is predominantly expressed in immune cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors. JAK3 mediates signaling events in both innate and adaptive immunity and plays a critical role in hematopoiesis during T-cells development (PMID: 14615376, PMID: 28513593). In the cytoplasm, JAK3 plays a crucial role in signal transduction via its association with type I receptors sharing the common gamma chain (γc) (PMID: 10075926). Following ligand binding to cell surface receptors, JAK3 phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins (PMID: 7481768). JAK3 phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then translocate to the nucleus to activate gene transcription (UniProtKB/Swiss-Prot). Mutations in this gene are associated with autosomal recessive severe combined immunodeficiency and are found throughout all 7 functional domains of the protein with different functional effects. In summary, JAK3 is definitively associated with autosomal recessive, severe combined immunodeficiency disease (T-negative/B-positive type). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time This classification was approved by the ClinGen SCID-CID Working Group on 12/17/20 (SOP Version 8).

T-B+ severe combined immunodeficiency due to JAK3 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010938

Submitter: PanelApp Australia

T-B+ severe combined immunodeficiency due to JAK3 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010938

Submitter: G2P

Clinical Genomic Database (CGD)

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, natural killer cell-negativeAR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; BMT has been reported as effective for T-cell reconstitution, but less succesful as relates to B and NK-cell function

Refs: 7659163; 7481768; 14615376; 21184155; 21732012; 23001410

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to JAK3 variants in ClinVar

11 Conditions Cataloged

T-B+ severe combined immunodeficiency due to JAK3 deficiencyTotal: 1154

not providedTotal: 110

Inborn genetic diseasesTotal: 83

not specifiedTotal: 75

Severe combined immunodeficiency diseaseTotal: 21

JAK3-related disorderTotal: 18

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positiveTotal: 2

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiencyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000215.4. 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		2 clinvar	8 clinvar	410 clinvar	9 clinvar	429
missense	7 clinvar	20 clinvar	333 clinvar	23 clinvar	6 clinvar	389
nonsense	32 clinvar	9 clinvar	1 clinvar			42
start loss						0
frameshift	30 clinvar	12 clinvar	1 clinvar			43
splice donor/acceptor (+/-2bp)	8 clinvar	16 clinvar	2 clinvar			26
Total	77	59	345	433	15	929

Highest pathogenic variant AF is 0.000040891333

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000215.4	RefSeq	NP_000206.2	23	MANE Select
ENST00000458235.7	Ensembl	ENSP00000391676.1	23	MANE Select
NM_001440439.1	RefSeq	NP_001427368.1	23	Standard
ENST00000526008.6	Ensembl	ENSP00000513006.1	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
jak3	Danio rerio	Structure: pro-T cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

jak3

Danio rerio

Structure: pro-T cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Primary immunodeficiency - Homo sapiens (human)
Non-small cell lung cancer - Homo sapiens (human)
Jak-STAT signaling pathway - Homo sapiens (human)
Chemokine signaling pathway - Homo sapiens (human)

Biological Process

MAPK cascade
adaptive immune response
negative regulation of dendritic cell cytokine production
protein phosphorylation
enzyme linked receptor protein signaling pathway

Molecular Function

protein tyrosine kinase activity
non-membrane spanning protein tyrosine kinase activity
Ras guanyl-nucleotide exchange factor activity
protein binding
ATP binding

Cellular Component

endosome
cytosol
cytoskeleton
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000458235
Coding exons: 23
Length: 23292
Individuals with no LoFs: 125713
Homozygous LoFs: 0
Heterozygous LoFs: 35
Defined: 125748
p: 0.000139

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.81	473	679	0.696	0.0000434	7178
Missense (PolyPhen)		129	239.65	0.53829		2670
Synonymous	2.18	245	292	0.838	0.0000185	2331
Loss of Function	4.34	19	53.1	0.357	0.00000281	572

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00015	0.00012	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000064	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00019	0.00018	rare
South Asian	0.00020	0.00020	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. Following ligand binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A AND STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion. {ECO:0000269|PubMed:11909529, ECO:0000269|PubMed:20440074, ECO:0000269|PubMed:7662955, ECO:0000269|PubMed:8022485}.;
Disease: DISEASE: Severe combined immunodeficiency autosomal recessive T- cell-negative/B-cell-positive/NK-cell-negative (T(-)B(+)NK(-) SCID) [MIM:600802]: A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. {ECO:0000269|PubMed:10982185, ECO:0000269|PubMed:14615376, ECO:0000269|PubMed:7659163, ECO:0000269|PubMed:9354668, ECO:0000269|PubMed:9753072}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.135

Intolerance Scores

LoFtool: 0.159
RVIS EVS: -0.99
RVIS percentile EVS: 8.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.964

Gene Damage Prediction

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