TNFSF9
protein-codingTNF superfamily member 9, the group of Tumor necrosis factor superfamily
Gene summary
The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This transmembrane cytokine is a bidirectional signal transducer that acts as a ligand for TNFRSF9/4-1BB, which is a costimulatory receptor molecule in T lymphocytes. This cytokine and its receptor are involved in the antigen presentation process and in the generation of cytotoxic T cells. The receptor TNFRSF9/4-1BB is absent from resting T lymphocytes but rapidly expressed upon antigenic stimulation. The ligand encoded by this gene, TNFSF9/4-1BBL, has been shown to reactivate anergic T lymphocytes in addition to promoting T lymphocyte proliferation. This cytokine has also been shown to be required for the optimal CD8 responses in CD8 T cells. This cytokine is expressed in carcinoma cell lines, and is thought to be involved in T cell-tumor cell interaction.[provided by RefSeq, Oct 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0015979
Submitter: PanelApp Australia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TNFSF9 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003811.4. 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 | 0 | |||||
| missense | 43 | 2 | 1 | 46 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 44 | 2 | 1 | 47 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003802.1 | 3 | MANE Select | |
| Ensembl | ENSP00000245817.2 | 3 | MANE Select | |
| Ensembl | ENSP00000792712.1 | 2 | Standard | |
| Ensembl | ENSP00000802383.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cytokine-cytokine receptor interaction - Homo sapiens (human)
- miR-targeted genes in leukocytes - TarBase
- miR-targeted genes in lymphocytes - TarBase
- Factors and pathways affecting insulin-like growth factor (IGF1)-Akt signaling
- the 41bb-dependent immune response
Biological Process
- apoptotic process
- immune response
- signal transduction
- cell-cell signaling
- cell population proliferation
Molecular Function
- signaling receptor binding
- cytokine activity
- tumor necrosis factor receptor binding
- tumor necrosis factor receptor superfamily binding
Cellular Component
- extracellular space
- plasma membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000245817
- Coding exons
- 3
- Length
- 4922
- Individuals with no LoFs
- 125638
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 125639
- p
- 0.00000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.480 | 169 | 152 | 1.11 | 0.00000892 | 1527 |
| Missense (PolyPhen) | 33 | 35.96 | 0.91769 | 359 | ||
| Synonymous | 0.130 | 79 | 80.5 | 0.982 | 0.00000497 | 619 |
| Loss of Function | 1.44 | 1 | 4.18 | 0.239 | 1.80e-7 | 43 |
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 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Cytokine that binds to TNFRSF9. Induces the proliferation of activated peripheral blood T-cells. May have a role in activation-induced cell death (AICD). May play a role in cognate interactions between T-cells and B-cells/macrophages. {ECO:0000269|PubMed:20032458}.;
Recessive Scores
- pRec
- 0.169
Intolerance Scores
- LoFtool
- 0.0631
- RVIS EVS
- 0.82
- RVIS percentile EVS
- 87.87
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.824
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |