TNFSF11

protein-coding

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

Gene summary

This gene encodes a member of the tumor necrosis factor (TNF) cytokine family which is a ligand for osteoprotegerin and functions as a key factor for osteoclast differentiation and activation. This protein was shown to be a dendritic cell survival factor and is involved in the regulation of T cell-dependent immune response. T cell activation was reported to induce expression of this gene and lead to an increase of osteoclastogenesis and bone loss. This protein was shown to activate antiapoptotic kinase AKT/PKB through a signaling complex involving SRC kinase and tumor necrosis factor receptor-associated factor (TRAF) 6, which indicated this protein may have a role in the regulation of cell apoptosis. Targeted disruption of the related gene in mice led to severe osteopetrosis and a lack of osteoclasts. The deficient mice exhibited defects in early differentiation of T and B lymphocytes, and failed to form lobulo-alveolar mammary structures during pregnancy. [provided by RefSeq, Mar 2026]

MANE transcript

NM_003701.4

Inheritance

ClinVar variants

P:4U:97B:97

Top phenotype

Osteopetrosis, autosomal recessive 2

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr13:42,562,736-42,608,013

External References & Databases

Ensembl (ENSG00000120659)

Transcript & Mutation Effects

hg38 • Region Span ~45.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive osteopetrosis 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009816

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive osteopetrosis 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009816

Submitter: ClinGen

TNFSF11 gene is located on chromosome 13 at 13q14.11 and encodes the tumor necrosis factor ligand superfamily member 11 protein which plays a crucial role in several biological processes, particularly in bone remodeling, immune function, and the formation of mammary glands during pregnancy (PMIDs: 37893470, 32850393). One disease assertion has been reported in association with this gene: osteopetrosis, autosomal recessive 2 (MIM:259710, MONDO:0009816). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in molecular mechanism, phenotypic variability, and inheritance pattern. Therefore the following disease entity has been lumped into one entity: TNFSF11 and TNFSF11-related osteopetrosis (MONDO: ID requested). TNFSF11 was first reported in connection with TNFSF11-related osteopetrosis in 2007 (Sobacchi et al. 2007 PMID: 17632511). Patients with this disease may present with optic atrophy, blindness, cranial nerve involvement, hydrocephalus, severe cerebral bulbar deterioration, severe growth inhibition, severely impaired and/or delayed dentition with chronic parotid/mandibular abscess, short stature, hepatosplenomegaly, anemia, hypocalcemic seizure, and hypocalcemia (PMID: 34056870). Six variants (2 frameshifts, 2 missense, 1 deletion, 1 splice site) reported in four publications have been included in this curation (PIMDs: 39011244, 34056870, 23762088, 17632511). This gene-disease relationship is also supported by two non-human model organisms (PMIDs: 10984520, 22068587), protein interaction (PMID: 22664871), biochemical function (PMID: 32850393), skeletal and extraskeletal expression (PMID: 9568710), and rescue in a non-human model organism (PMID: 23762088). In summary, there is definitive evidence supporting the relationship between TNFSF11 and TNFSF11-related osteopetrosis. The classification was approved by the ClinGen Skeletal Disorders GCEP on meeting date 12/02/2024 (SOP Version 11)

autosomal recessive osteopetrosis 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009816

Submitter: Genomics England PanelApp

autosomal recessive osteopetrosis 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009816

Submitter: PanelApp Australia

autosomal recessive osteopetrosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019026

Submitter: Orphanet

autosomal recessive osteopetrosis 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009816

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Osteopetrosis, autosomal recessive 2AR

Manifestation: Audiologic/Otolaryngologic; Dental; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Hematologic; Musculoskeletal

Rationale: Individuals may present early in life with audiologic, neurologic, and ophthalmologic manifestations including hydrocephalus and visual impairment, as well as other findings including hepatosplenomegaly and fractures with poor bone remodeling, and awareness of complications may allow surveillance and prompt treatment; HSCT has been reported as beneficial

Refs: 17632511

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TNFSF11 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 188

Inborn genetic diseasesTotal: 36

Autosomal recessive osteopetrosis 2Total: 33

not specifiedTotal: 21

TNFSF11-related disorderTotal: 10

Disorder of boneTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003701.4. 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			3 clinvar	86 clinvar	3 clinvar	92
missense	1 clinvar		88 clinvar	6 clinvar	2 clinvar	97
nonsense		1 clinvar				1
start loss			4 clinvar			4
frameshift	2 clinvar		1 clinvar			3
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	3	1	97	92	5	198

Highest pathogenic variant AF is 6.840488e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003701.4	RefSeq	NP_003692.1	5	MANE Select
ENST00000398795.7	Ensembl	ENSP00000381775.3	5	MANE Select
NM_033012.4	RefSeq	NP_143026.1	4	Standard
ENST00000358545.6	Ensembl	ENSP00000351347.2	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Breast cancer - Homo sapiens (human)
Prolactin signaling pathway - Homo sapiens (human)
Rheumatoid arthritis - Homo sapiens (human)
Osteoclast differentiation - Homo sapiens (human)
NF-kappa B signaling pathway - Homo sapiens (human)

Biological Process

ossification
osteoclast proliferation
monocyte chemotaxis
immune response
activation of JUN kinase activity

Molecular Function

cytokine activity
tumor necrosis factor receptor binding
protein binding
tumor necrosis factor receptor superfamily binding

Cellular Component

extracellular region
extracellular space
cytoplasm
plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000239849
Coding exons: 5
Length: 45278
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125742
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.929	139	173	0.802	0.00000859	2054
Missense (PolyPhen)		27	46.064	0.58614		562
Synonymous	-1.02	78	67.4	1.16	0.00000346	611
Loss of Function	1.96	6	13.9	0.432	6.56e-7	169

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK. Osteoclast differentiation and activation factor. Augments the ability of dendritic cells to stimulate naive T-cell proliferation. May be an important regulator of interactions between T-cells and dendritic cells and may play a role in the regulation of the T-cell-dependent immune response. May also play an important role in enhanced bone-resorption in humoral hypercalcemia of malignancy (PubMed:22664871). Induces osteoclastogenesis by activating multiple signaling pathways in osteoclast precursor cells, chief among which is induction of long lasting oscillations in the intracellular concentration of Ca (2+) resulting in the activation of NFATC1, which translocates to the nucleus and induces osteoclast-specific gene transcription to allow differentiation of osteoclasts. During osteoclast differentiation, in a TMEM64 and ATP2A2-dependent manner induces activation of CREB1 and mitochondrial ROS generation necessary for proper osteoclast generation (By similarity). {ECO:0000250|UniProtKB:O35235, ECO:0000269|PubMed:22664871}.;
Disease: DISEASE: Osteopetrosis, autosomal recessive 2 (OPTB2) [MIM:259710]: 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. OPTB2 is characterized by paucity of osteoclasts, suggesting a molecular defect in osteoclast development. {ECO:0000269|PubMed:17632511}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.882

Intolerance Scores

LoFtool: 0.0717
RVIS EVS: -0.09
RVIS percentile EVS: 46.74

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.278

Gene Damage Prediction

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