Autosomal recessive osteopetrosis 7

Summary

Autosomal recessive osteopetrosis 7 (MONDO:0012859) is a disease caused by TNFRSF11A (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TNFRSF11A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 106

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive osteopetrosis 7
Mondo ID	MONDO:0012859
MeSH	C567354
OMIM	612301
Orphanet	178389
DOID	DOID:0110946
UMLS	C2676766
MedGen	436770
GARD	0010106
Is cancer (heuristic)	no

Also known as: autosomal recessive osteoclast-poor osteopetrosis with hypogammaglobulinemia · autosomal recessive osteopetrosis type 7 · OPTB7 · osteopetrosis (disease) caused by mutation in TNFRSF11A · osteopetrosis autosomal recessive 7 · osteopetrosis osteoclast-poor with hypogammaglobulinemia · osteopetrosis, autosomal recessive 7 · osteopetrosis, autosomal recessive type 7 · osteopetrosis-hypogammaglobulinemia syndrome · TNFRSF11A osteopetrosis (disease)

Data availability: 106 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › autosomal recessive osteopetrosis 7

Related subtypes (46): hypersensitivity reaction disease, immune system cancer, immune system organ benign neoplasm, bone marrow disorder, thymus gland disorder, inborn error of immunity, leukocyte disorder, psoriasis, spondyloarthropathy, aggressive insulitis, benign insulitis, inflammatory bowel disease, autoimmune disease, TNF receptor 1-associated periodic fever syndrome, epidermodysplasia verruciformis, Vici syndrome, proteosome-associated autoinflammatory syndrome, hyperimmunoglobulinemia D with periodic fever, transcobalamin II deficiency, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, granulomatosis with polyangiitis, graft versus host disease, congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome, Roifman syndrome, cryopyrin-associated periodic syndrome, anti-HLA hyperimmunization, acquired immunodeficiency, erythroderma desquamativum, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, familial Mediterranean fever, 22q11.2 deletion syndrome, T-cell large granular lymphocyte leukemia, twin to twin transfusion syndrome, immunodeficiency disease, immunoproliferative disorder, cytokine receptor deficiency, immunodeficiency-related disorder, phagocytic cell dysfunction, thrombocytopenic purpura, lymphoid system disorder, immune reconstitution inflammatory syndrome, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, cytokine release syndrome, early-onset autoimmunity-autoinflammation-immunodeficiency syndrome, CADINS disease, autoinflammation, panniculitis, and dermatosis syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

106 retrieved; paginated sample, class counts are floors:

56 uncertain significance, 15 conflicting classifications of pathogenicity, 11 benign, 8 pathogenic, 7 benign/likely benign, 5 likely pathogenic, 4 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064753	NC_000018.10:g.60033942_60033993del		Pathogenic	no assertion criteria provided
1684671	NM_003839.4(TNFRSF11A):c.1530dup (p.Ser511fs)	TNFRSF11A	Pathogenic	criteria provided, single submitter
2444185	NM_003839.4(TNFRSF11A):c.54C>A (p.Cys18Ter)	TNFRSF11A	Pathogenic	criteria provided, single submitter
2574148	NM_003839.4(TNFRSF11A):c.239G>A (p.Trp80Ter)	TNFRSF11A	Pathogenic	criteria provided, single submitter
6301	NM_003839.4(TNFRSF11A):c.508A>G (p.Arg170Gly)	TNFRSF11A	Pathogenic	no assertion criteria provided
6302	NM_003839.4(TNFRSF11A):c.523T>C (p.Cys175Arg)	TNFRSF11A	Pathogenic	no assertion criteria provided
6304	NM_003839.4(TNFRSF11A):c.730G>T (p.Ala244Ser)	TNFRSF11A	Pathogenic	criteria provided, single submitter
6305	NM_003839.4(TNFRSF11A):c.157G>C (p.Gly53Arg)	TNFRSF11A	Pathogenic	no assertion criteria provided
1684669	NM_003839.4(TNFRSF11A):c.147A>C (p.Lys49Asn)	TNFRSF11A	Likely pathogenic	criteria provided, single submitter
1684670	NM_003839.4(TNFRSF11A):c.380G>A (p.Cys127Tyr)	TNFRSF11A	Likely pathogenic	criteria provided, single submitter
2500800	NM_003839.4(TNFRSF11A):c.328dup (p.Arg110fs)	TNFRSF11A	Likely pathogenic	criteria provided, single submitter
2572028	NM_003839.4(TNFRSF11A):c.443A>T (p.Asp148Val)	TNFRSF11A	Likely pathogenic	criteria provided, single submitter
4812937	NM_003839.4(TNFRSF11A):c.1075C>T (p.Gln359Ter)	TNFRSF11A	Likely pathogenic	criteria provided, single submitter
890490	NM_003839.4(TNFRSF11A):c.33G>C (p.Leu11=)	LOC130062628	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1442005	NM_003839.4(TNFRSF11A):c.637G>A (p.Gly213Ser)	TNFRSF11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
287370	NM_003839.4(TNFRSF11A):c.718A>G (p.Lys240Glu)	TNFRSF11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
287597	NM_003839.4(TNFRSF11A):c.1254T>G (p.Ser418=)	TNFRSF11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327728	NM_003839.4(TNFRSF11A):c.402G>A (p.Ala134=)	TNFRSF11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327732	NM_003839.4(TNFRSF11A):c.543A>T (p.Arg181Ser)	TNFRSF11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327733	NM_003839.4(TNFRSF11A):c.555T>C (p.His185=)	TNFRSF11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327734	NM_003839.4(TNFRSF11A):c.954C>T (p.Tyr318=)	TNFRSF11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327735	NM_003839.4(TNFRSF11A):c.999C>T (p.Thr333=)	TNFRSF11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
713429	NM_003839.4(TNFRSF11A):c.1279G>A (p.Asp427Asn)	TNFRSF11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
724616	NM_003839.4(TNFRSF11A):c.525T>C (p.Cys175=)	TNFRSF11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
888869	NM_003839.4(TNFRSF11A):c.447A>G (p.Thr149=)	TNFRSF11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
888934	NM_003839.4(TNFRSF11A):c.731-11G>A	TNFRSF11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
891049	NM_003839.4(TNFRSF11A):c.284-4G>A	TNFRSF11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
891349	NM_003839.4(TNFRSF11A):c.*1060C>T	TNFRSF11A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327724	NM_003839.4(TNFRSF11A):c.29C>T (p.Pro10Leu)	LOC130062628	Uncertain significance	criteria provided, multiple submitters, no conflicts
888782	NM_003839.4(TNFRSF11A):c.-22G>T	LOC130062628	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TNFRSF11A	Strong	Autosomal recessive	autosomal recessive osteopetrosis 7	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNFRSF11A	Orphanet:1782	Dysosteosclerosis
TNFRSF11A	Orphanet:178389	Osteopetrosis-hypogammaglobulinemia syndrome
TNFRSF11A	Orphanet:2801	Juvenile Paget disease
TNFRSF11A	Orphanet:391490	Adult-onset myasthenia gravis
TNFRSF11A	Orphanet:85195	Familial expansile osteolysis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNFRSF11A	HGNC:11908	ENSG00000141655	Q9Y6Q6	Tumor necrosis factor receptor superfamily member 11A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNFRSF11A	Tumor necrosis factor receptor superfamily member 11A	Receptor for TNFSF11/RANKL/TRANCE/OPGL; essential for RANKL-mediated osteoclastogenesis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNFRSF11A	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_11, TNFR_11A

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	1
mucosa of sigmoid colon	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNFRSF11A	221	broad	marker	parotid gland, mucosa of sigmoid colon, jejunal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TNFRSF11A	1,186

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNFRSF11A	Q9Y6Q6	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	1	671.8×	0.003	TNFRSF11A
TNFR2 non-canonical NF-kB pathway	1	181.3×	0.006	TNFRSF11A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of fever generation by positive regulation of prostaglandin secretion	1	8426.0×	0.002	TNFRSF11A
circadian temperature homeostasis	1	5617.3×	0.002	TNFRSF11A
multinuclear osteoclast differentiation	1	5617.3×	0.002	TNFRSF11A
cellular response to zinc ion starvation	1	2407.4×	0.003	TNFRSF11A
positive regulation of bone resorption	1	991.3×	0.004	TNFRSF11A
mammary gland alveolus development	1	991.3×	0.004	TNFRSF11A
lymph node development	1	802.5×	0.004	TNFRSF11A
response to tumor necrosis factor	1	624.1×	0.004	TNFRSF11A
monocyte chemotaxis	1	581.1×	0.004	TNFRSF11A
positive regulation of osteoclast differentiation	1	581.1×	0.004	TNFRSF11A
response to interleukin-1	1	510.7×	0.005	TNFRSF11A
osteoclast differentiation	1	343.9×	0.006	TNFRSF11A
tumor necrosis factor-mediated signaling pathway	1	330.4×	0.006	TNFRSF11A
response to mechanical stimulus	1	300.9×	0.006	TNFRSF11A
positive regulation of non-canonical NF-kappaB signal transduction	1	255.3×	0.007	TNFRSF11A
response to insulin	1	230.8×	0.007	TNFRSF11A
ossification	1	227.7×	0.007	TNFRSF11A
positive regulation of JNK cascade	1	163.6×	0.009	TNFRSF11A
response to ethanol	1	146.5×	0.009	TNFRSF11A
response to lipopolysaccharide	1	124.8×	0.010	TNFRSF11A
positive regulation of ERK1 and ERK2 cascade	1	85.1×	0.014	TNFRSF11A
adaptive immune response	1	84.3×	0.014	TNFRSF11A
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.016	TNFRSF11A
cell-cell signaling	1	69.6×	0.016	TNFRSF11A
positive regulation of cell population proliferation	1	33.6×	0.031	TNFRSF11A
signal transduction	1	16.1×	0.062	TNFRSF11A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TNFRSF11A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TNFRSF11A

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TNFRSF11A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.