TNFRSF11A

Chr 18ADAR

TNF receptor superfamily member 11a

Also known as: CD265, FEO, LOH18CR1, ODFR, OFE, OPTB7, OSTS, PDB2

NCBI Gene: 8792 ENSG00000141655 UniProt: Q9Y6Q6 OMIM: 603499

The encoded protein is a TNF receptor superfamily member that serves as the receptor for RANKL and is essential for osteoclast formation and bone remodeling. Mutations cause bone disorders with both autosomal dominant and autosomal recessive inheritance patterns, including early-onset Paget disease, familial expansile osteolysis, and osteopetrosis. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.597), and the associated bone diseases can present in childhood.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAD/ARLOEUF 0.603 OMIM phenotypes

Clinical Summary— TNFRSF11A

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.60LOEUF

pLI 0.009

Z-score 3.05

OE 0.33 (0.19–0.60)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

1.29Z-score

OE missense 0.81 (0.73–0.89)

279 obs / 346.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.33 (0.19–0.60)

0≤0.351.4

Missense OE0.81 (0.73–0.89)

0≤0.61.4

Synonymous OE0.85

0≤1.21.6

LoF obs/exp: 8 / 24.2Missense obs/exp: 279 / 346.5Syn Z: 1.42

0.76top 25%

GOF

0.81top 10%

LOF

0.3065th %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 · 1 literature citation

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.

Literature Evidence

GOFOur findings: i) reveal that JPD can be associated with an activating mutation within TNFRSF11A, ii) expand the range and overlap of phenotypes among the Mendelian disorders of RANK activation, and iii) call for mutation analysis to improve diagnosis, prognostication, recurrence risk assessment, andPMID:25063546

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