OSTM1

protein-coding

osteoclastogenesis associated transmembrane protein 1

Gene summary

This gene encodes a protein that may be involved in the degradation of G proteins via the ubiquitin-dependent proteasome pathway. The encoded protein binds to members of subfamily A of the regulator of the G-protein signaling (RGS) family through an N-terminal leucine-rich region. This protein also has a central RING finger-like domain and E3 ubiquitin ligase activity. This protein is highly conserved from flies to humans. Defects in this gene may cause the autosomal recessive, infantile malignant form of osteopetrosis. [provided by RefSeq, Jul 2008]

MANE transcript

NM_014028.4

Inheritance

ClinVar variants

P:27U:102B:117

Top phenotype

Osteopetrosis, autosomal recessive 5

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr6:108,029,245-108,165,854

External References & Databases

Ensembl (ENSG00000081087)

Transcript & Mutation Effects

hg38 • Region Span ~136.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive osteopetrosis 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009817

Submitter: Genomics England PanelApp

autosomal recessive osteopetrosis 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009817

Submitter: PanelApp Australia

infantile osteopetrosis with neuroaxonal dysplasiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010866

Submitter: Orphanet

autosomal recessive osteopetrosis 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009817

Submitter: ClinGen

*OSTM1* was first reported in relation to autosomal recessive osteoporosis in 2003 (Chalhoub et al., PMID: 12627228). 6 variants (splice site, nonsense, frameshift, missense) that have been reported in at least 9 probands in 7 publications (PMIDs: 12627228, 15108279, 16813530, 17400532, 17922613, 19507210, 23772242) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (interaction, biochemical functional, and functional alteration evidence, as well as a mouse model; PMIDs: 12627228, 16525474, 16813530, 18296023). OSTM1 interacts with CLCN7 by co-localizing and assembling into a structure that includes both proteins. CLCN7 has been classified as definitive for both autosomal dominant and autosomal recessive osteopetrosis by the Skeletal Disorders GCEP. Biochemical functional and functional alteration evidence show that OSTM1 is necessary in signaling processes associated with bone development. The mouse model shows that mutant mice have osteoporosis, early lethality, and brain anomalies, just like affected humans. In summary, there is definitive evidence supporting the relationship between *OSTM1* and autosomal recessive osteopetrosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date June 10th, 2024 (SOP Version 10).

autosomal recessive osteopetrosis 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009817

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Osteopetrosis, autosomal recessive 5AR

Manifestation: Hematologic; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: HSCT has been described

Refs: 3513575; 10325711; 12627228; 15177004; 15108279; 16813530; 17922613; 17985267; 19507210

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OSTM1 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 275

Inborn genetic diseasesTotal: 50

Autosomal recessive osteopetrosis 5Total: 30

OSTM1-related disorderTotal: 5

not specifiedTotal: 4

OsteopetrosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014028.4. 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				108 clinvar	2 clinvar	110
missense		1 clinvar	98 clinvar	5 clinvar	2 clinvar	106
nonsense	11 clinvar	2 clinvar				13
start loss		1 clinvar				1
frameshift	8 clinvar	1 clinvar	1 clinvar			10
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	3 clinvar			6
Total	20	7	102	113	4	246

Highest pathogenic variant AF is 0.000010265057

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014028.4	RefSeq	NP_054747.2	6	MANE Select
ENST00000193322.8	Ensembl	ENSP00000193322.3	6	MANE Select
ENST00000440575.6	Ensembl	ENSP00000398556.2	5	Standard
ENST00000467960.2	Ensembl	ENSP00000514449.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Stimuli-sensing channels
Ion channel transport
Transport of small molecules

Biological Process

osteoclast differentiation

Cellular Component

lysosomal membrane
cytosol
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000193322
Coding exons: 6
Length: 124446
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125736
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.09	139	180	0.771	0.00000855	2159
Missense (PolyPhen)		36	60.194	0.59806		727
Synonymous	0.0508	72	72.5	0.992	0.00000320	647
Loss of Function	2.33	6	16.1	0.373	9.12e-7	174

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for osteoclast and melanocyte maturation and function. {ECO:0000250, ECO:0000269|PubMed:21527911}.;
Disease: DISEASE: Osteopetrosis, autosomal recessive 5 (OPTB5) [MIM:259720]: 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. OPTB5 patients manifest primary central nervous system involvement in addition to the classical stigmata of severe bone sclerosis, growth failure, anemia, thrombocytopenia and visual impairment with optic atrophy. {ECO:0000269|PubMed:12627228, ECO:0000269|PubMed:16813530}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.181

Intolerance Scores

LoFtool: 0.492
RVIS EVS: -0.36
RVIS percentile EVS: 28.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.734

Gene Damage Prediction

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