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

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptors can interact with various TRAF family proteins, through which this receptor induces the activation of NF-kappa B and MAPK8/JNK. This receptor and its ligand are important regulators of the interaction between T cells and dendritic cells. This receptor is also an essential mediator for osteoclast and lymph node development. Mutations at this locus have been associated with familial expansile osteolysis, autosomal recessive osteopetrosis, and Paget disease of bone. Alternatively spliced transcript variants have been described for this locus. [provided by RefSeq, Aug 2012]

OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

35 unique Pathogenic / Likely Pathogenic· 453 VUS of 796 total submissions

Explore recent and relevant literature in Research Assistant →

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 OE?0.33 (0.19–0.60)

0≤0.351.4

Missense OE?0.81 (0.73–0.89)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

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

This gene — mechanism propensity

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, and1

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

References

1.PMID 25063546 ↗

ClinVar Variant Classifications

796 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23

Likely Pathogenic12

VUS453

Likely Benign225

Benign42

Conflicting29

Pathogenic

Likely Pathogenic

453

VUS

225

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	15	6	2	0	23
Likely Pathogenic	7	5	0	0	12
VUS	11	377	59	6	453
Likely Benign	1	11	71	142	225
Benign	0	2	36	4	42
Conflicting	—				29
Total	34	401	168	152	784

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

View in ClinVar →

89 pathogenic / likely-pathogenic (of 93) ClinVar copy-number / structural variants overlap TNFRSF11A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →