TNFRSF11A

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

Basic information

Region (hg38): 18:62325287-62391288

Previous symbols: [ "PDB2", "LOH18CR1" ]

Links

ENSG00000141655 ∙ NCBI:8792 ∙ OMIM:603499 ∙ HGNC:11908 ∙ Uniprot:Q9Y6Q6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• osteosarcoma (Limited), mode of inheritance: AD
• autosomal recessive osteopetrosis 7 (Strong), mode of inheritance: AR
• dysosteosclerosis (Supportive), mode of inheritance: AR
• familial expansile osteolysis (Supportive), mode of inheritance: AD
• autosomal recessive osteopetrosis 7 (Supportive), mode of inheritance: AR
• familial expansile osteolysis (Moderate), mode of inheritance: AD
• autosomal recessive osteopetrosis 7 (Moderate), mode of inheritance: AR
• dysosteosclerosis (Limited), mode of inheritance: AR
• Paget disease of bone 2, early-onset (Strong), mode of inheritance: AD
• autosomal recessive osteopetrosis 7 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Familial expansile osteolysis; Paget disease of bone 2, early-onset; Osteopetrosis, autosomal recessive 7	AD/AR	Allergy/Immunology/Infectious; Endocrine; Musculoskeletal; Oncologic	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	Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Craniofacial; Dental; Endocrine; Musculoskeletal; Oncologic	3346299; 2530018; 9626117; 10615125; 11123042; 18606301; 18328984; 18672105; 19940926; 22271396

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TNFRSF11A gene.

• not provided (11 variants)
• Autosomal recessive osteopetrosis 7 (4 variants)
• Familial expansile osteolysis;Paget disease of bone 2, early-onset (1 variants)
• Familial expansile osteolysis (1 variants)
• Paget disease of bone 2, early-onset (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TNFRSF11A gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			8	105	4	117
missense	1	3	268	8	2	282
nonsense	5		1			6
start loss			2			2
frameshift	7	2	6			15
inframe indel	2	1	10			13
splice donor/acceptor (+/-2bp)		2				2
splice region			12	13		25
non coding			42	49	34	125
Total	15	8	337	162	40

Highest pathogenic variant AF is 0.0000265

Variants in TNFRSF11A

This is a list of pathogenic ClinVar variants found in the TNFRSF11A region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
18-62325304-G-A		Osteopetrosis • Bone Paget disease	Uncertain significance (Jun 14, 2016)
18-62325314-G-A		not specified • Osteopetrosis • Bone Paget disease	Benign/Likely benign (Jun 19, 2021)
18-62325331-G-T		Autosomal recessive osteopetrosis 7 • Paget disease of bone 2, early-onset	Uncertain significance (Jan 12, 2018)
18-62325344-T-C		not specified • Bone Paget disease • Osteopetrosis	Benign/Likely benign (Jun 19, 2021)
18-62325353-A-G			Uncertain significance (Sep 05, 2023)
18-62325354-T-C			Uncertain significance (Dec 08, 2022)
18-62325355-G-T		Inborn genetic diseases	Likely pathogenic (Jul 12, 2024)
18-62325358-C-G		not specified • Autosomal recessive osteopetrosis 7 • Paget disease of bone 2, early-onset	Benign (Feb 01, 2024)
18-62325360-C-G			Uncertain significance (Jan 23, 2024)
18-62325363-GCGCCCGGCGGCGC-G			Pathogenic (Sep 17, 2023)
18-62325366-C-T		Autosomal recessive osteopetrosis 7 • Paget disease of bone 2, early-onset • Inborn genetic diseases	Uncertain significance (Apr 20, 2024)
18-62325368-C-A			Uncertain significance (Feb 10, 2022)
18-62325368-C-G		Inborn genetic diseases	Uncertain significance (Jan 08, 2024)
18-62325369-G-A			Uncertain significance (Mar 13, 2022)
18-62325369-G-T			Uncertain significance (Oct 08, 2023)
18-62325372-G-A			Uncertain significance (Apr 09, 2023)
18-62325373-G-C			Likely benign (Jan 24, 2023)
18-62325376-C-G			Likely benign (Nov 28, 2021)
18-62325376-C-T			Likely benign (Jan 11, 2022)
18-62325381-C-G			Uncertain significance (Jun 16, 2023)
18-62325381-C-T		Autosomal recessive osteopetrosis 7 • Paget disease of bone 2, early-onset • TNFRSF11A-related disorder	Uncertain significance (Feb 01, 2024)
18-62325385-G-C		Autosomal recessive osteopetrosis 7 • Paget disease of bone 2, early-onset	Conflicting classifications of pathogenicity (Dec 07, 2023)
18-62325386-T-TTCGCGCTGCTGCTGCTCTGCGCGCTGC		Paget disease of bone 2, early-onset	Pathogenic (Aug 31, 2023)
18-62325387-T-TCGCGCTGCTGCTGCTCTG		Familial expansile osteolysis • Paget disease of bone 2, early-onset;Familial expansile osteolysis	Pathogenic (Jul 26, 2021)
18-62325389-G-A			Uncertain significance (Dec 09, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TNFRSF11A	protein_coding	protein_coding	ENST00000586569	10	65997

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00877	0.991	125736	0	12	125748	0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.29	279	347	0.805	0.0000209	3967
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000203	0.000203
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000360	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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);Osteoclast Signaling;RANKL-RANK (Receptor activator of NFKB (ligand)) Signaling Pathway;TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway;TNFR2 non-canonical NF-kB pathway;Cytokine Signaling in Immune system;Immune System;bone remodeling;RANKL (Consensus)

Intolerance Scores

• loftool: 0.261
• rvis_EVS: 0.67
• rvis_percentile_EVS: 84.61

Haploinsufficiency Scores

• pHI: 0.0838
• hipred: Y
• hipred_score: 0.597
• ghis: 0.434

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.533

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tnfrsf11a
• Phenotype: respiratory system phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); hematopoietic system phenotype; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); neoplasm; digestive/alimentary phenotype; limbs/digits/tail phenotype; immune system phenotype; skeleton phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; craniofacial phenotype; homeostasis/metabolism phenotype; cellular phenotype

Gene ontology

• Biological process: ossification;adaptive immune response;monocyte chemotaxis;signal transduction;cell-cell signaling;positive regulation of cell population proliferation;response to radiation;osteoclast differentiation;response to lipopolysaccharide;tumor necrosis factor-mediated signaling pathway;response to cytokine;response to tumor necrosis factor;positive regulation of JUN kinase activity;positive regulation of bone resorption;lymph node development;positive regulation of DNA-binding transcription factor activity;positive regulation of NF-kappaB transcription factor activity;circadian temperature homeostasis;mammary gland alveolus development;response to interleukin-1;positive regulation of fever generation by positive regulation of prostaglandin secretion;TNFSF11-mediated signaling pathway;positive regulation of ERK1 and ERK2 cascade via TNFSF11-mediated signaling;multinuclear osteoclast differentiation
• Cellular component: cytosol;plasma membrane;external side of plasma membrane;integral component of membrane
• Molecular function: transmembrane signaling receptor activity;tumor necrosis factor-activated receptor activity;protein binding;cytokine binding;signaling receptor activity;metal ion binding