TNFSF13
protein-codingTNF superfamily member 13, the group of CD molecules|Tumor necrosis factor superfamily
Gene summary
The protein encoded by this gene is a member of the tumor necrosis factor (TNF) ligand family. This protein is a ligand for TNFRSF17/BCMA, a member of the TNF receptor family. This protein and its receptor are both found to be important for B cell development. In vitro experiments suggested that this protein may be able to induce apoptosis through its interaction with other TNF receptor family proteins such as TNFRSF6/FAS and TNFRSF14/HVEM. Alternative splicing results in multiple transcript variants. Some transcripts that skip the last exon of the upstream gene (TNFSF12) and continue into the second exon of this gene have been identified; 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 ~3.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0015977
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0015517
Submitter: ClinGen
*TNFSF13*, encoding the APRIL protein, was first reported in relation to common variable immunodeficiency in 2020 by Yeh et al. (PMID: 32298700). This is the only report of a patient with an APRIL deficiency caused by a homozygous *TNFSF13* null mutation (NM_003808.4:c.508del (p.Leu170CysfsTer5)) resulting in hypogammaglobulinemia with a markedly reduced level of plasmacytes in peripheral blood and a clearly increased level of circulating marginal zone B cells. This gene-disease relationship is supported by experimental evidence; the role of APRIL as a proliferation-inducing ligand which works in B cell maturation and maintenance (Yu G, et al., 2000, PMID: 10973284) through interaction with TACI (PMID: 10973284), and its enhanced expression in monocytes of healthy controls (PMID: 32298700) is consistent with the resulting CVID in the patient with absent expression. Functional alteration was also observed in patient B-cell and monocyte-derived dendritic cell coculture assays which mirrored clinical findings in patients (PMID: 32298700). The immunologic manifestations in the patient showed some overlap with APRIL-/- mice (PMID: 18180376), although additional APRIL-/- mice were reported to have no gross abnormalities, in the immune system or otherwise (PMID: 14729948, 14988498). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TNFSF13 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003808.4. 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 | 1 | 1 | 1 | 3 | ||
| missense | 10 | 10 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 1 | 11 | 1 | 1 | 14 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003799.1 | 6 | MANE Select | |
| Ensembl | ENSP00000343505.4 | 6 | MANE Select | |
| RefSeq | NP_001185551.1 | 5 | Standard | |
| RefSeq | NP_001185552.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Rheumatoid arthritis - Homo sapiens (human)
- Cytokine-cytokine receptor interaction - Homo sapiens (human)
- Intestinal immune network for IgA production - Homo sapiens (human)
- Spinal Cord Injury
- yaci and bcma stimulation of b cell immune responses
Biological Process
- immune response
- signal transduction
- positive regulation of cell population proliferation
- regulation of signaling receptor activity
- tumor necrosis factor-mediated signaling pathway
Molecular Function
- signaling receptor binding
- cytokine activity
- tumor necrosis factor receptor binding
Cellular Component
- extracellular region
- nucleoplasm
- cytoplasm
- cytosol
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000338784
- Coding exons
- 6
- Length
- 3317
- Individuals with no LoFs
- 125729
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 12
- Defined
- 125741
- p
- 0.0000477
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.526 | 121 | 138 | 0.874 | 0.00000722 | 1596 |
| Missense (PolyPhen) | 29 | 51.536 | 0.56272 | 603 | ||
| Synonymous | -0.200 | 59 | 57.1 | 1.03 | 0.00000311 | 530 |
| Loss of Function | 3.02 | 2 | 14.4 | 0.139 | 7.97e-7 | 143 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00043 | 0.00043 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Cytokine that binds to TNFRSF13B/TACI and to TNFRSF17/BCMA. Plays a role in the regulation of tumor cell growth. May be involved in monocyte/macrophage-mediated immunological processes. {ECO:0000269|PubMed:10973284}.;
Recessive Scores
- pRec
- 0.504
Intolerance Scores
- LoFtool
- 0.200
- RVIS EVS
- 0.17
- RVIS percentile EVS
- 65.56
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.539
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |