TNFRSF4

Chr 1

TNF receptor superfamily member 4

Also known as: ACT35, CD134, IMD16, OX40, TXGP1L

NCBI Gene: 7293 ENSG00000186827 UniProt: P43489

The TNFRSF4 protein is a TNF receptor superfamily member that serves as a costimulatory receptor for T-cell activation and promotes T-cell survival by suppressing apoptosis through NF-kappaB signaling. Mutations cause autosomal recessive immunodeficiency 16, characterized by defective T-cell responses and impaired T cell-dependent B cell function. The gene shows low constraint against loss-of-function variants (pLI 0.0001, LOEUF 1.32), consistent with the recessive inheritance pattern requiring biallelic mutations for disease manifestation.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been shown to activate NF-kappaB through its interaction with adaptor proteins TRAF2 and TRAF5. Knockout studies in mice suggested that this receptor promotes the expression of apoptosis inhibitors BCL2 and BCL2lL1/BCL2-XL, and thus suppresses apoptosis. The knockout studies also suggested the roles of this receptor in CD4+ T cell response, as well as in T cell-dependent B cell proliferation and differentiation. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtImmunodeficiency 16

Clinical highlights

Gene-disease validity (ClinGen)

combined immunodeficiency due to OX40 deficiency · ARLimitednot for standalone diagnostic reporting

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.32

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.32LOEUF

pLI 0.000

Z-score 0.86

OE 0.71 (0.40–1.32)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.62Z-score

OE missense 0.86 (0.75–0.99)

142 obs / 164.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.71 (0.40–1.32)

0≤0.351.4

Missense OE?0.86 (0.75–0.99)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 7 / 9.9Missense obs/exp: 142 / 164.5Syn Z: 0.16

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

TNFRSF4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Diabetic Nephropathies

A Pilot Study of Fenofibrate to Prevent Kidney Function Loss in Type 1 Diabetes

ACTIVE NOT RECRUITING

NCT04929379Phase PHASE2Alessandro DoriaStarted 2022-01-04

FenofibratePlacebo

Triple Negative Breast Cancer

Neoadjuvant INBRX-106 in Combination With Pembrolizumab for Stage II/III TNBC Patients

RECRUITING

NCT06353997Phase PHASE2Providence Health & ServicesStarted 2024-09-05

PembrolizumabINBRX-106

Solid TumorNon-Small Cell Lung CancerHead and Neck Cancer

Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab (Keytruda®) in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)

RECRUITING

NCT04198766Phase PHASE1, PHASE2Inhibrx Biosciences, IncStarted 2019-12-10

INBRX-106 - Hexavalent OX40 agonist antibodypembrolizumab 200 mgpembrolizumab 400 mg

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3

PubTator3

Identification and validation of TNFRSF4 as a high-profile biomarker for prognosis and immunomodulation in endometrial carcinoma

Ma H et al.·BMC Cancer

2022