TNFSF4

Chr 1

TNF superfamily member 4

Also known as: CD134L, CD252, GP34, OX-40L, OX4OL, TNLG2B, TXGP1

NCBI Gene: 7292 ENSG00000117586 UniProt: P23510

The protein is a cytokine that binds to TNFRSF4 and co-stimulates T-cell proliferation and cytokine production, functioning in T cell-antigen presenting cell interactions and mediating adhesion of activated T cells to endothelial cells. Mutations in this gene are associated with susceptibility to myocardial infarction with autosomal dominant inheritance. The gene is not highly constrained against loss-of-function variants, suggesting tolerance to such changes.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a cytokine of the tumor necrosis factor (TNF) ligand family. The encoded protein functions in T cell antigen-presenting cell (APC) interactions and mediates adhesion of activated T cells to endothelial cells. Polymorphisms in this gene have been associated with Sjogren's syndrome and systemic lupus erythematosus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ResearchGenerating clinical summary…

DNmechanismLOEUF 1.68

Clinical Summary— TNFSF4

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Population Constraint (gnomAD)

Low constraint (pLI 0.05) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

12 VUS of 21 total submissions

Explore recent and relevant literature in Research Assistant →

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?

1.68LOEUF

pLI 0.049

Z-score 0.65

OE 0.61 (0.24–1.68)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.92Z-score

OE missense 0.73 (0.60–0.89)

68 obs / 93.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.61 (0.24–1.68)

0≤0.351.4

Missense OE?0.73 (0.60–0.89)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 2 / 3.3Missense obs/exp: 68 / 93.1Syn Z: 0.58

This gene — mechanism propensity

0.6454th %ile

GOF

0.6052th %ile

LOF

0.2872th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

21 submitted variants in ClinVar

ClinVar

Classification Summary

VUS12

Likely Benign3

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	12	0	12
Likely Benign	1	2	3
Benign	0	1	1
Total	13	3	16

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

32 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap TNFSF4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →