TNFSF11

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

Basic information

Region (hg38): 13:42562735-42608013

Links

ENSG00000120659 ∙ ∙ OMIM:602642 ∙ HGNC:11926 ∙ Uniprot:O14788 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal recessive osteopetrosis 2 (Strong), mode of inheritance: AR
• autosomal recessive osteopetrosis 2 (Strong), mode of inheritance: AR
• autosomal recessive osteopetrosis (Supportive), mode of inheritance: AR
• autosomal recessive osteopetrosis 2 (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Osteopetrosis, autosomal recessive 2	AR	Hematologic; Musculoskeletal	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	Audiologic/Otolaryngologic; Dental; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Ophthalmologic	17632511

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TNFSF11 gene.

• not provided (144 variants)
• Autosomal recessive osteopetrosis 2 (64 variants)
• Inborn genetic diseases (10 variants)
• not specified (7 variants)
• Increased bone mineral density (6 variants)
• Osteopetrosis (1 variants)
• TNFSF11-related condition (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TNFSF11 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			3	44	4	51
missense			69	2	2	73
nonsense		1				1
start loss			4			4
frameshift	1					1
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region			3	4		7
non coding			26	10	12	48
Total	1	1	103	56	18

Variants in TNFSF11

This is a list of pathogenic ClinVar variants found in the TNFSF11 region.

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

Position	Type	Phenotype	Significance	ClinVar
13-42573888-T-C			Benign (Nov 12, 2018)
13-42574157-C-T		Autosomal recessive osteopetrosis 2	Uncertain significance (Jan 12, 2018)
13-42574160-G-C		Autosomal recessive osteopetrosis 2	Uncertain significance (Jan 13, 2018)
13-42574163-C-T		Autosomal recessive osteopetrosis 2	Likely benign (Jan 12, 2018)
13-42574177-C-G		Autosomal recessive osteopetrosis 2	Benign (Jun 19, 2021)
13-42574200-C-T		Autosomal recessive osteopetrosis 2	Uncertain significance (Jan 13, 2018)
13-42574210-C-T		Autosomal recessive osteopetrosis 2	Uncertain significance (Apr 27, 2017)
13-42574223-C-A		Autosomal recessive osteopetrosis 2	Uncertain significance (Jan 13, 2018)
13-42574230-C-T		Autosomal recessive osteopetrosis 2	Uncertain significance (Jan 12, 2018)
13-42574240-C-G		Autosomal recessive osteopetrosis 2	Uncertain significance (Jan 13, 2018)
13-42574297-G-C		Autosomal recessive osteopetrosis 2	Uncertain significance (Jan 12, 2018)
13-42574300-C-T		Autosomal recessive osteopetrosis 2	Uncertain significance (Jan 12, 2018)
13-42574305-T-A			Uncertain significance (Jun 04, 2022)
13-42574305-T-C		Autosomal recessive osteopetrosis 2	Uncertain significance (Jul 05, 2022)
13-42574305-T-G		Autosomal recessive osteopetrosis 2	Uncertain significance (Jun 28, 2022)
13-42574306-G-A			Uncertain significance (Sep 21, 2021)
13-42574312-C-A			Likely benign (Oct 31, 2020)
13-42574312-C-G			Likely benign (Aug 09, 2023)
13-42574316-A-G			Uncertain significance (Aug 02, 2022)
13-42574319-A-G			Uncertain significance (Sep 12, 2022)
13-42574327-C-T			Likely benign (Dec 23, 2022)
13-42574331-A-G			Uncertain significance (Aug 30, 2023)
13-42574333-G-A			Likely benign (Jan 31, 2024)
13-42574333-G-C			Uncertain significance (Mar 13, 2022)
13-42574340-C-G			Uncertain significance (Mar 11, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TNFSF11	protein_coding	protein_coding	ENST00000239849	5	45278

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00492	0.970	125736	0	6	125742	0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.929	139	173	0.802	0.00000859	2054
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000152	0.000152
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000176	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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);Cytokine-cytokine receptor interaction - Homo sapiens (human);Osteoclast Signaling;RANKL-RANK (Receptor activator of NFKB (ligand)) Signaling Pathway;Differentiation Pathway;Vitamin D Receptor Pathway;Osteoblast Signaling;TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway;TNFR2 non-canonical NF-kB pathway;Cytokine Signaling in Immune system;Immune System;TNFs bind their physiological receptors;bone remodeling;IL6-mediated signaling events (Consensus)

Recessive Scores

• pRec: 0.882

Intolerance Scores

• loftool: 0.0717
• rvis_EVS: -0.09
• rvis_percentile_EVS: 46.74

Haploinsufficiency Scores

• pHI: 0.493
• hipred: N
• hipred_score: 0.458

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.278

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tnfsf11
• Phenotype: muscle phenotype; craniofacial phenotype; homeostasis/metabolism 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); growth/size/body region phenotype; hematopoietic system phenotype; neoplasm; endocrine/exocrine gland phenotype; limbs/digits/tail phenotype; vision/eye phenotype; immune system phenotype; skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; normal 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); reproductive system phenotype

Gene ontology

• Biological process: ossification;osteoclast proliferation;monocyte chemotaxis;immune response;activation of JUN kinase activity;regulation of signaling receptor activity;cytokine-mediated signaling pathway;calcium-mediated signaling;osteoclast differentiation;tumor necrosis factor-mediated signaling pathway;mammary gland epithelial cell proliferation;positive regulation of homotypic cell-cell adhesion;osteoclast development;paracrine signaling;positive regulation of I-kappaB kinase/NF-kappaB signaling;positive regulation of MAP kinase activity;tooth eruption;bone resorption;positive regulation of osteoclast differentiation;positive regulation of bone resorption;positive regulation of transcription by RNA polymerase II;positive regulation of T cell activation;positive regulation of DNA-binding transcription factor activity;positive regulation of NF-kappaB transcription factor activity;protein homooligomerization;positive regulation of corticotropin-releasing hormone secretion;positive regulation of protein kinase B signaling;calcium ion homeostasis;mammary gland alveolus development;ERK1 and ERK2 cascade;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;positive regulation of intracellular signal transduction;cellular response to leukemia inhibitory factor;positive regulation of osteoclast development
• Cellular component: extracellular region;extracellular space;cytoplasm;plasma membrane;integral component of plasma membrane
• Molecular function: cytokine activity;tumor necrosis factor receptor binding;protein binding;tumor necrosis factor receptor superfamily binding