JAK3

Janus kinase 3, the group of Jak family tyrosine kinases

Basic information

Region (hg38): 19:17824779-17848071

Links

ENSG00000105639 ∙ NCBI:3718 ∙ OMIM:600173 ∙ HGNC:6193 ∙ Uniprot:P52333 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• T-B+ severe combined immunodeficiency due to JAK3 deficiency (Definitive), mode of inheritance: AR
• T-B+ severe combined immunodeficiency due to JAK3 deficiency (Supportive), mode of inheritance: AR
• T-B+ severe combined immunodeficiency due to JAK3 deficiency (Definitive), mode of inheritance: AR
• T-B+ severe combined immunodeficiency due to JAK3 deficiency (Strong), mode of inheritance: AR
• T-B+ severe combined immunodeficiency due to JAK3 deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, natural killer cell-negative	AR	Allergy/Immunology/Infectious	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	Allergy/Immunology/Infectious	7659163; 7481768; 14615376; 21184155; 21732012; 23001410

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the JAK3 gene.

• T-B+ severe combined immunodeficiency due to JAK3 deficiency (756 variants)
• not provided (133 variants)
• not specified (64 variants)
• Severe combined immunodeficiency disease (21 variants)
• Inborn genetic diseases (18 variants)
• Acute megakaryoblastic leukemia (4 variants)
• JAK3-related condition (3 variants)
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (2 variants)
• Leukemoid reaction (2 variants)
• Lymphoblastic leukemia, acute, with lymphomatous features (2 variants)
• - (1 variants)
• 6 conditions (1 variants)
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (1 variants)
• Adenoid cystic carcinoma (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the JAK3 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		1	11	176	10	198
missense	5	13	250	18	4	290
nonsense	14	3				17
start loss						0
frameshift	14	4	1			19
inframe indel	1		6			7
splice donor/acceptor (+/-2bp)	6	10	1			17
splice region	1		17	33	2	53
non coding		2	44	105	83	234
Total	40	33	313	299	97

Highest pathogenic variant AF is 0.0000263

Variants in JAK3

This is a list of pathogenic ClinVar variants found in the JAK3 region.

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

Position	Type	Phenotype	Significance	ClinVar
19-17824811-CA-C		Severe combined immunodeficiency disease	Conflicting classifications of pathogenicity (Apr 01, 2023)
19-17824817-T-C		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Benign (Jan 12, 2018)
19-17824908-C-T		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Uncertain significance (Jan 12, 2018)
19-17824910-C-T		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Uncertain significance (Jan 12, 2018)
19-17824956-G-T		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Uncertain significance (Jan 12, 2018)
19-17824965-T-C		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Uncertain significance (Jan 12, 2018)
19-17824982-A-T		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Likely benign (Jan 13, 2018)
19-17824991-T-C		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Uncertain significance (Jan 12, 2018)
19-17825082-A-C		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Uncertain significance (Jan 12, 2018)
19-17825195-G-A		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Likely benign (Jan 13, 2018)
19-17825212-A-G		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Uncertain significance (Jan 13, 2018)
19-17825220-G-A		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Uncertain significance (Jan 13, 2018)
19-17825221-G-A		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Uncertain significance (Jan 12, 2018)
19-17825234-C-A		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Uncertain significance (Jan 15, 2018)
19-17825321-C-T		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Benign (Jan 13, 2018)
19-17825345-C-G		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Uncertain significance (Jan 13, 2018)
19-17825389-G-GA		Severe combined immunodeficiency disease	Uncertain significance (Jun 14, 2016)
19-17825424-C-T		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Benign (Jan 12, 2018)
19-17825450-G-A		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Benign (Jan 13, 2018)
19-17825456-T-A		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Uncertain significance (Jan 12, 2018)
19-17825479-C-G		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Uncertain significance (Jan 12, 2018)
19-17825525-G-T		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Uncertain significance (Jan 12, 2018)
19-17825546-C-T		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Likely benign (Jan 12, 2018)
19-17825649-C-G		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Uncertain significance (Jan 13, 2018)
19-17825705-T-C		T-B+ severe combined immunodeficiency due to JAK3 deficiency	Benign (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
JAK3	protein_coding	protein_coding	ENST00000458235	23	23292

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000593	1.00	125713	0	35	125748	0.000139

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.81	473	679	0.696	0.0000434	7178
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000274	0.000244
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000644	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.000189	0.000185
Middle Eastern	0.0000644	0.0000544
South Asian	0.000204	0.000196
Other	0.000166	0.000163

dbNSFP

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.
• Pathway: 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);HTLV-I infection - Homo sapiens (human);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Necroptosis - Homo sapiens (human);Th17 cell differentiation - Homo sapiens (human);Th1 and Th2 cell differentiation - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Measles - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);JAK-STAT-Core;IL-7 Signaling Pathway;IL-9 Signaling Pathway;Oncostatin M Signaling Pathway;IL-4 Signaling Pathway;Chemokine signaling pathway;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;PI3K-Akt Signaling Pathway;MET in type 1 papillary renal cell carcinoma;IL-2 Signaling Pathway;Signaling by GPCR;Interleukin-4 and 13 signaling;Interleukin-7 signaling;Signal Transduction;Signaling by Interleukins;il 2 signaling pathway;stat3 signaling pathway;il-7 signal transduction;il-2 receptor beta chain in t cell activation;il 4 signaling pathway;il 6 signaling pathway;role of erbb2 in signal transduction and oncology;Cytokine Signaling in Immune system;JAK STAT MolecularVariation 1;TCR;Interleukin-9 signaling;Immune System;Interleukin-15 signaling;Interleukin receptor SHC signaling;Interleukin-2 family signaling;KitReceptor;IL-2 signaling;IL-7 signaling;IL-4 signaling;SHP2 signaling;JAK STAT MolecularVariation 2;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;Signaling events mediated by TCPTP;JAK STAT pathway and regulation;IL2;EPO signaling;IL2-mediated signaling events;Interleukin-2 signaling;IL4;Leptin;IL-7;VEGF;G beta:gamma signalling through PI3Kgamma;G-protein beta:gamma signalling;GPCR downstream signalling;IL9;IL2 signaling events mediated by STAT5;CD40/CD40L signaling;IL2 signaling events mediated by PI3K;IL4-mediated signaling events;Interleukin-3, 5 and GM-CSF signaling (Consensus)

Recessive Scores

• pRec: 0.135

Intolerance Scores

• loftool: 0.159
• rvis_EVS: -0.99
• rvis_percentile_EVS: 8.56

Haploinsufficiency Scores

• hipred: Y
• hipred_score: 0.694
• ghis: 0.645

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.964

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Jak3
• Phenotype: cellular phenotype; endocrine/exocrine gland phenotype; immune system phenotype; vision/eye phenotype; digestive/alimentary phenotype; pigmentation 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); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: jak3
• Affected structure: pro-T cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: MAPK cascade;adaptive immune response;negative regulation of dendritic cell cytokine production;protein phosphorylation;enzyme linked receptor protein signaling pathway;tyrosine phosphorylation of STAT protein;peptidyl-tyrosine phosphorylation;cytokine-mediated signaling pathway;B cell differentiation;erythrocyte differentiation;negative regulation of interleukin-10 production;negative regulation of interleukin-12 production;intracellular signal transduction;interleukin-15-mediated signaling pathway;interleukin-4-mediated signaling pathway;interleukin-2-mediated signaling pathway;interleukin-7-mediated signaling pathway;interleukin-9-mediated signaling pathway;interleukin-21-mediated signaling pathway;positive regulation of T cell proliferation;T cell homeostasis;innate immune response;negative regulation of FasL biosynthetic process;negative regulation of T-helper 1 cell differentiation;regulation of JAK-STAT cascade;negative regulation of T cell activation;JAK-STAT cascade involved in growth hormone signaling pathway;regulation of T cell apoptotic process;negative regulation of thymocyte apoptotic process;response to interleukin-2;response to interleukin-4;response to interleukin-15;response to interleukin-9
• Cellular component: endosome;cytosol;cytoskeleton;plasma membrane
• Molecular function: protein tyrosine kinase activity;non-membrane spanning protein tyrosine kinase activity;Ras guanyl-nucleotide exchange factor activity;protein binding;ATP binding;protein phosphatase binding