TNFRSF6B

Chr 20

TNF receptor superfamily member 6b

NCBI Gene: 8771 ENSG00000243509 UniProt: O95407 OMIM: 603361

The encoded protein functions as a decoy receptor that neutralizes cytotoxic ligands including FASL and LIGHT, thereby protecting cells against apoptosis. This gene is extremely tolerant to loss-of-function variants (pLI near 0, LOEUF 1.77), and no Mendelian diseases have been definitively associated with TNFRSF6B mutations in pediatric patients.

OMIM ResearchSummary from RefSeq, UniProt

Soluble decoy receptor that binds and neutralizes the TNF-family ligands TNFSF14/LIGHT, TNFSF15, and FASLG, preventing them from interacting with their cognate receptors and thereby blocking apoptosis and other immune-signaling pathway

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.77

Clinical Summary— TNFRSF6B

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.77LOEUF

pLI 0.000

Z-score -0.15

OE 1.06 (0.61–1.77)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.30Z-score

OE missense 1.26 (1.13–1.40)

250 obs / 198.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.06 (0.61–1.77)

0≤0.351.4

Missense OE?1.26 (1.13–1.40)

0≤0.61.4

Synonymous OE?1.59

0≤1.21.6

LoF obs/exp: 8 / 7.6Missense obs/exp: 250 / 198.6Syn Z: -4.41

This gene — mechanism propensity

0.6454th %ile

GOF

0.7028th %ile

LOF

0.3356th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

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.