JAK1
protein-codingJanus kinase 1, the group of FERM domain containing|Jak family tyrosine kinases
Gene summary
This gene encodes a membrane protein that is a member of a class of protein-tyrosine kinases (PTK) characterized by the presence of a second phosphotransferase-related domain immediately N-terminal to the PTK domain. The encoded kinase phosphorylates STAT proteins (signal transducers and activators of transcription) and plays a key role in interferon-alpha/beta, interferon-gamma, and cytokine signal transduction. This gene plays a crucial role in effecting the expression of genes that mediate inflammation, epithelial remodeling, and metastatic cancer progression. This gene is a key component of the interleukin-6 (IL-6)/JAK1/STAT3 immune and inflammation response and is a therapeutic target for alleviating cytokine storms. The kinase activity of this gene is directly inhibited by the suppressor of cytokine signalling 1 (SOCS1) protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2020]
- JAK1B
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~234.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0033558
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0033558
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0033558
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0033558
Submitter: ClinGen
Autosomal dominant *JAK1*-related immune dysregulation was first reported in2017 (Del Bel KL, et al., 2017, PMID: 28111307). JAK1 is activated by a broad range of cytokines and can phosphorylate any STAT. The JAK/STAT pathway plays an integral role in extracellular cytokine and growth factor signaling, as well as in controlling hematopoiesis and immune function. *JAK1* gain-of-function variants result in a systemic immune dysregulatory condition, with clinical features including autoimmunity with skin inflammation, eosinophilia, impairment of growth, and liver abnormalities. Ten missense variants have been reported in 10 probands and one case-control study in 6 publications (PMIDs: 28111307, 30940614, 32750333, 35046931, 37343845, 38563820). This gene-disease relationship is further supported by experimental evidence including its biochemical function (PMID: 8232552), which is hyperactive in patients (PMIDs: 28111307, 32750333, 37343845, and PMID:38563820), and multiple model organisms that recapitulate aspects of the disease (PMIDs: 36546480, 35046931, 23791841). In summary, there is Definitive evidence to support the relationship between *JAK1* and autosomal dominant immune dysregulation. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0033558
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: Individuals have been described as being affected by manifestations such as atopic dermatitis and chronic gastrointestinal inflammation, and medical management (with JAK inhibitors such as ruxolitinib and tofacitinib) has been described as clinically beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to JAK1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002227.4. 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 | 6 | 229 | 7 | 242 | ||
| missense | 2 | 3 | 356 | 10 | 371 | |
| nonsense | 2 | 1 | 3 | |||
| start loss | 1 | 1 | ||||
| frameshift | 3 | 3 | ||||
| splice donor/acceptor (+/-2bp) | 10 | 10 | ||||
| Total | 2 | 3 | 378 | 240 | 7 | 630 |
Highest pathogenic variant AF is 0.000002052301
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002218.2 | 24 | MANE Select | |
| Ensembl | ENSP00000343204.4 | 24 | MANE Select | |
| RefSeq | NP_001307852.1 | 24 | Standard | |
| RefSeq | NP_001308781.1 | 24 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| jak1 | 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)
- Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
- Jak-STAT signaling pathway - Homo sapiens (human)
- Influenza A - Homo sapiens (human)
- HTLV-I infection - Homo sapiens (human)
Biological Process
- MAPK cascade
- protein phosphorylation
- peptidyl-tyrosine phosphorylation
- cytokine-mediated signaling pathway
- intracellular signal transduction
Molecular Function
- protein tyrosine kinase activity
- non-membrane spanning protein tyrosine kinase activity
- Ras guanyl-nucleotide exchange factor activity
- growth hormone receptor binding
- protein binding
Cellular Component
- nucleus
- cytoplasm
- endosome
- cytosol
- cytoskeleton
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000342505
- Coding exons
- 24
- Length
- 133276
- Individuals with no LoFs
- 124680
- Homozygous LoFs
- 5
- Heterozygous LoFs
- 109
- Defined
- 124794
- p
- 0.000457
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.61 | 332 | 667 | 0.498 | 0.0000380 | 7712 |
| Missense (PolyPhen) | 92 | 276.47 | 0.33276 | 3318 | ||
| Synonymous | 0.470 | 243 | 253 | 0.962 | 0.0000154 | 2077 |
| Loss of Function | 6.44 | 7 | 61.4 | 0.114 | 0.00000311 | 739 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000065 | 0.000065 | rare |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000062 | 0.000062 | rare |
| South Asian | 0.0033 | 0.0031 | notable |
| Other | 0.00099 | 0.00099 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway (PubMed:7615558). Kinase partner for the interleukin (IL)-2 receptor (PubMed:11909529). {ECO:0000269|PubMed:11909529, ECO:0000269|PubMed:7615558}.;
Recessive Scores
- pRec
- 0.174
Intolerance Scores
- LoFtool
- 0.168
- RVIS EVS
- -1.33
- RVIS percentile EVS
- 4.69
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.975
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |