TNFSF12
protein-codingTNF superfamily member 12, 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 protein is a ligand for the FN14/TWEAKR receptor. This cytokine has overlapping signaling functions with TNF, but displays a much wider tissue distribution. This cytokine, which exists in both membrane-bound and secreted forms, can induce apoptosis via multiple pathways of cell death in a cell type-specific manner. This cytokine is also found to promote proliferation and migration of endothelial cells, and thus acts as a regulator of angiogenesis. Alternative splicing results in multiple transcript variants. Some transcripts skip the last exon of this gene and continue into the second exon of the neighboring TNFSF13 gene; such read-through transcripts are contained in GeneID 407977, TNFSF12-TNFSF13. [provided by RefSeq, Oct 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~9.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0003778
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0015517
Submitter: ClinGen
TNFSF12 (i.e., TWEAK) was first reported in relation to autosomal dominant common variable immunodeficiency in 2013 (Wang HY et al., PMID: 23493554). One missense variant reported in one proband that also segregated with disease in two additional family members was included in this curation (PMID: 23493554). The affected family members presented with increased risk of respiratory infections and immune features, including hypogammaglobulinemia and abnormal B- and T-cell populations. The mechanism of pathogenicity is unknown. This gene-disease association is also supported by a mouse model and in vitro studies in cell lines (PMIDs: 9405449, 9560343, 12411489, 16325585, 23493554). TNFSF12 is expressed in a wide range of tissues and cells, including human spleen, lymph nodes, and immune cells (PMID: 9405449, 12411489), and it can be found as both a transmembrane protein and secreted cytokine (PMID: 29038621). Upregulation of TNFSF12 and its receptor FN14 (i.e., TWEAKR) has been found to occur in response to inflammation (PMID: 24636536). In addition, the TNFSF12/FN14 pathway has multiple functions, such as in regulation of skeletal muscle cell progenitor proliferation and differentiation (PMID: 17124496) and cutaneous inflammation, including as a critical contributor to the chronic inflammatory skin condition psoriasis (PMID: 30038329). Furthermore, TNFSF12 regulates NFkB activity, apoptosis, and proliferation in immune cells (PMID: 9405449, 9560343, 12411489). The presence of a patient-derived TNFSF12 variant resulted in decreased apoptosis of and NFkB activity in cell lines compared ot WT TNFSF12, while exposure of B cells to the mutant TNFSF12 protein with BAFF resulted in decreased B-cell proliferation compared to WT TNFSF12 (PMID: 23493554). A TNFSF12-/- mouse model displayed T-cell defects, but other features of TNFSF12-associated disease were not assessed (PMID: 16325585). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TNFSF12 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003809.3. 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 | 68 | 2 | 72 | ||
| missense | 128 | 1 | 129 | |||
| nonsense | 5 | 5 | ||||
| start loss | 0 | |||||
| frameshift | 3 | 3 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 139 | 69 | 2 | 210 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003800.1 | 7 | MANE Select | |
| Ensembl | ENSP00000293825.6 | 7 | MANE Select | |
| Ensembl | ENSP00000314636.7 | 6 | Standard | |
| Ensembl | ENSP00000514755.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cytokine-cytokine receptor interaction - Homo sapiens (human)
- TNF related weak inducer of apoptosis (TWEAK) Signaling Pathway
- TWEAK
- induction of apoptosis through dr3 and dr4/5 death receptors
- TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway
Biological Process
- angiogenesis
- positive regulation of endothelial cell proliferation
- apoptotic process
- immune response
- signal transduction
Molecular Function
- signaling receptor binding
- cytokine activity
- tumor necrosis factor receptor binding
- protein binding
Cellular Component
- extracellular region
- extracellular space
- plasma membrane
- integral component of plasma membrane
- perinuclear region of cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000557233
- Coding exons
- 11
- Length
- 12718
- Individuals with no LoFs
- 124514
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 15
- Defined
- 124529
- p
- 0.0000602
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.983 | 137 | 173 | 0.790 | 0.0000101 | 2068 |
| Missense (PolyPhen) | 31 | 55.131 | 0.56229 | 612 | ||
| Synonymous | -0.330 | 74 | 70.5 | 1.05 | 0.00000413 | 699 |
| Loss of Function | 3.60 | 4 | 22.4 | 0.178 | 0.00000137 | 222 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00043 | 0.00043 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000061 | 0.000054 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000027 | 0.000027 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Binds to FN14 and possibly also to TNRFSF12/APO3. Weak inducer of apoptosis in some cell types. Mediates NF-kappa-B activation. Promotes angiogenesis and the proliferation of endothelial cells. Also involved in induction of inflammatory cytokines. Promotes IL8 secretion. {ECO:0000269|PubMed:10085077, ECO:0000269|PubMed:23667509}.;
Recessive Scores
- pRec
- 0.504
Intolerance Scores
- LoFtool
- 0.174
- RVIS EVS
- -0.21
- RVIS percentile EVS
- 38.28
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.0777