TNFSF11
TNF superfamily member 11, the group of CD molecules|Tumor necrosis factor superfamily
Basic information
Region (hg38): 13:42562736-42608013
Links
Phenotypes
GenCC
Source:
- 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:
| 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
- not_provided (176 variants)
- Autosomal_recessive_osteopetrosis_2 (36 variants)
- Inborn_genetic_diseases (33 variants)
- TNFSF11-related_disorder (9 variants)
- Increased_bone_mineral_density (5 variants)
- not_specified (4 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. These statistics are base on transcript: NM_000003701.4. Only rare variants are included in the table.
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.
| Effect | PathogenicP | Likely pathogenicLP | VUSVUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 77 | 84 | ||||
| missense | 84 | 92 | ||||
| nonsense | 1 | |||||
| start loss | 4 | 4 | ||||
| frameshift | 2 | |||||
| splice donor/acceptor (+/-2bp) | 1 | |||||
| Total | 3 | 1 | 93 | 82 | 5 |
Highest pathogenic variant AF is 6.84049e-7
Loading clinvar variants...
GnomAD
Source:
| 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:
- 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
- ghis
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