TNFRSF11A

protein-coding

TNF receptor superfamily member 11a, the group of CD molecules|Tumor necrosis factor receptor superfamily

Gene summary

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]

Previous symbols:

PDB2
LOH18CR1

MANE transcript

NM_003839.4

Inheritance

AR, AD

ClinVar variants

P:33U:396B:188

Top phenotype

Familial expansile osteolysis; Paget disease of bone 2, early-onset; Osteopetrosis, autosomal recessive 7

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr18:62,325,287-62,391,288

External References & Databases

Ensembl (ENSG00000141655)

Transcript & Mutation Effects

hg38 • Region Span ~66.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive osteopetrosis 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012859

Submitter: PanelApp Australia

dysosteosclerosisLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009138

Submitter: Ambry Genetics

autosomal recessive osteopetrosis 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012859

Submitter: Ambry Genetics

Paget disease of bone 2, early-onsetSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011183

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive osteopetrosis 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012859

Submitter: Genomics England PanelApp

Paget disease of bone 2, early-onsetMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011183

Submitter: Ambry Genetics

familial expansile osteolysisMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008275

Submitter: Ambry Genetics

osteosarcomaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0009807

Submitter: Genomics England PanelApp

dysosteosclerosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009138

Submitter: Orphanet

autosomal recessive osteopetrosis 7SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012859

Submitter: Orphanet

autosomal recessive osteopetrosis 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012859

Submitter: Labcorp Genetics (formerly Invitae)

familial expansile osteolysisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008275

Submitter: Orphanet

Clinical Genomic Database (CGD)

Familial expansile osteolysis; Paget disease of bone 2, early-onset; Osteopetrosis, autosomal recessive 7AD/AR

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Craniofacial; Dental; Endocrine; Musculoskeletal; Oncologic

Intervention: Allergy/Immunology/Infectious; Endocrine; Musculoskeletal; Oncologic

Rationale: In Osteopetrosis, autosomal recessive 7, individuals can present with hypocalcemic seizures, which are responsive to treatment; Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; In Polyostotic osteolytic dysplasia, hereditary expansile, HSCT has been reported as effective, including when performed in late infancy; For Paget disease of bone, medical management (eg, inhibitors of osteoclastic bone resorption) can be beneficial - bisphosphonates are current first line of treatment, and awareness of the risk of related oncologic processes (eg, osteosarcoma) may be beneficial to allow early diagnosis and treatment

Refs: 3346299; 2530018; 9626117; 10615125; 11123042; 18606301; 18328984; 18672105; 19940926; 22271396

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TNFRSF11A variants in ClinVar

9 Conditions Cataloged

not providedTotal: 652

Inborn genetic diseasesTotal: 95

Autosomal recessive osteopetrosis 7Total: 57

not specifiedTotal: 42

Paget disease of bone 2, early-onsetTotal: 41

TNFRSF11A-related disorderTotal: 28

Familial expansile osteolysisTotal: 11

Disorder of boneTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003839.4. 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			6 clinvar	165 clinvar	1 clinvar	172
missense	5 clinvar	3 clinvar	377 clinvar	21 clinvar	1 clinvar	407
nonsense	6 clinvar	3 clinvar	3 clinvar			12
start loss		2 clinvar	2 clinvar			4
frameshift	8 clinvar	2 clinvar	7 clinvar			17
splice donor/acceptor (+/-2bp)		4 clinvar	1 clinvar			5
Total	19	14	396	186	2	617

Highest pathogenic variant AF is 0.000026529773

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003839.4	RefSeq	NP_003830.1	10	MANE Select
ENST00000586569.3	Ensembl	ENSP00000465500.1	10	MANE Select
NM_001270949.2	RefSeq	NP_001257878.1	9	Standard
NM_001270950.2	RefSeq	NP_001257879.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Prolactin signaling pathway - Homo sapiens (human)
Rheumatoid arthritis - Homo sapiens (human)
Osteoclast differentiation - Homo sapiens (human)
NF-kappa B signaling pathway - Homo sapiens (human)
Cytokine-cytokine receptor interaction - Homo sapiens (human)

Biological Process

ossification
adaptive immune response
monocyte chemotaxis
signal transduction
cell-cell signaling

Molecular Function

transmembrane signaling receptor activity
tumor necrosis factor-activated receptor activity
protein binding
cytokine binding
signaling receptor activity

Cellular Component

cytosol
plasma membrane
external side of plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000586569
Coding exons: 10
Length: 65997
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 125748
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.29	279	347	0.805	0.0000209	3967
Missense (PolyPhen)		72	109.26	0.65895		1218
Synonymous	1.42	126	148	0.851	0.0000103	1219
Loss of Function	3.05	8	24.2	0.331	0.00000105	308

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000036	0.000035	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for TNFSF11/RANKL/TRANCE/OPGL; essential for RANKL-mediated osteoclastogenesis. Involved in the regulation of interactions between T-cells and dendritic cells. {ECO:0000269|PubMed:9878548}.;
Disease: DISEASE: Paget disease of bone 2, early-onset (PDB2) [MIM:602080]: A 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. {ECO:0000269|PubMed:10615125}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Osteopetrosis, autosomal recessive 7 (OPTB7) [MIM:612301]: A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. Deafness and blindness are generally thought to represent effects of pressure on nerves. OPTB7 is characterized by paucity of osteoclasts, suggesting a molecular defect in osteoclast development. OPTB7 is associated with hypogammaglobulinemia. {ECO:0000269|PubMed:18606301}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.261
RVIS EVS: 0.67
RVIS percentile EVS: 84.61

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.533

Gene Damage Prediction

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