TNFRSF11B

protein-coding

TNF receptor superfamily member 11b, the group of Tumor necrosis factor receptor superfamily

Gene summary

The protein encoded by this gene is a member of the TNF-receptor superfamily. This protein is an osteoblast-secreted decoy receptor that functions as a negative regulator of bone resorption. This protein specifically binds to its ligand, osteoprotegerin ligand, both of which are key extracellular regulators of osteoclast development. Studies of the mouse counterpart also suggest that this protein and its ligand play a role in lymph-node organogenesis and vascular calcification. Alternatively spliced transcript variants of this gene have been reported, but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

Previous symbols:

MANE transcript

NM_002546.4

Inheritance

ClinVar variants

P:10U:136B:49

Top phenotype

Paget disease of bone 5, juvenile

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr8:118,923,557-118,951,885

External References & Databases

Ensembl (ENSG00000164761)

Transcript & Mutation Effects

hg38 • Region Span ~28.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

juvenile Paget diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009394

Submitter: Orphanet

juvenile Paget diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009394

Submitter: Labcorp Genetics (formerly Invitae)

juvenile Paget diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009394

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Paget disease of bone 5, juvenileAR

Manifestation: Dental; Endocrine; Musculoskeletal

Intervention: Endocrine; Musculoskeletal

Rationale: Individuals may present with manifestations including osteopenia, fractures, and progressive skeletal deformity, and medical treatment (eg, with disodium etidronate, bisphosphonates, osteoprotegerin) has been reported as beneficial

Refs: 13368018; 14123485; 5675396; 1593590; 8053403; 8770706; 12189164; 12124406; 14672344; 16135836; 17352649 ; 25108083

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TNFRSF11B variants in ClinVar

7 Conditions Cataloged

not providedTotal: 169

Inborn genetic diseasesTotal: 46

Hyperphosphatasemia with bone diseaseTotal: 38

not specifiedTotal: 11

TNFRSF11B-related disorderTotal: 5

ArthritisTotal: 1

Connective tissue disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002546.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	44 clinvar	3 clinvar	49
missense	2 clinvar	1 clinvar	128 clinvar	1 clinvar	1 clinvar	133
nonsense	3 clinvar	1 clinvar	3 clinvar			7
start loss						0
frameshift	2 clinvar	1 clinvar	2 clinvar			5
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	7	3	136	45	4	195

Highest pathogenic variant AF is 0.000003717569

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002546.4	RefSeq	NP_002537.3	5	MANE Select
ENST00000297350.9	Ensembl	ENSP00000297350.4	5	MANE Select
ENST00000517352.1	Ensembl	ENSP00000427924.1	3	Standard
ENST00000903853.1	Ensembl	ENSP00000573912.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Osteoclast differentiation - Homo sapiens (human)
Cytokine-cytokine receptor interaction - Homo sapiens (human)
Osteoclast Signaling
Apoptosis Modulation and Signaling
RANKL-RANK (Receptor activator of NFKB (ligand)) Signaling Pathway

Biological Process

skeletal system development
apoptotic process
signal transduction
response to nutrient
regulation of signaling receptor activity

Molecular Function

cytokine activity
protein binding
signaling receptor activity

Cellular Component

extracellular region
extracellular space
plasma membrane
extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000297350
Coding exons: 5
Length: 28644
Individuals with no LoFs: 125734
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 125748
p: 0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.841	184	219	0.840	0.0000123	2667
Missense (PolyPhen)		34	66.13	0.51414		863
Synonymous	0.570	80	86.8	0.922	0.00000562	711
Loss of Function	3.00	5	19.2	0.260	9.94e-7	229

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000073	0.000070	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as decoy receptor for TNFSF11/RANKL and thereby neutralizes its function in osteoclastogenesis. Inhibits the activation of osteoclasts and promotes osteoclast apoptosis in vitro. Bone homeostasis seems to depend on the local ratio between TNFSF11 and TNFRSF11B. May also play a role in preventing arterial calcification. May act as decoy receptor for TNFSF10/TRAIL and protect against apoptosis. TNFSF10/TRAIL binding blocks the inhibition of osteoclastogenesis. {ECO:0000269|PubMed:22664871, ECO:0000269|PubMed:9168977}.;
Disease: DISEASE: Paget disease of bone 5, juvenile-onset (PDB5) [MIM:239000]: An autosomal recessive, juvenile-onset form of Paget disease, a disorder of bone remodeling characterized by increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Osteoclastic overactivity followed by compensatory osteoblastic activity leads to a structurally disorganized mosaic of bone (woven bone), which is mechanically weaker, larger, less compact, more vascular, and more susceptible to fracture than normal adult lamellar bone. PDB5 clinical manifestations include short stature, progressive long bone deformities, fractures, vertebral collapse, skull enlargement, and hyperostosis with progressive deafness. {ECO:0000269|PubMed:12189164}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.603

Intolerance Scores

LoFtool: 0.211
RVIS EVS: -0.29
RVIS percentile EVS: 33.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.706

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium