BMP1

protein-coding

bone morphogenetic protein 1, the group of Astacins|Bone morphogenetic proteins

Gene summary

This gene encodes a protein that is capable of inducing formation of cartilage in vivo. Although other bone morphogenetic proteins are members of the TGF-beta superfamily, this gene encodes a protein that is not closely related to other known growth factors. This gene is expressed as alternatively spliced variants that share an N-terminal protease domain but differ in their C-terminal region. [provided by RefSeq, Aug 2008]

Previous symbols:

PCOLC

MANE transcript

NM_006129.5

Inheritance

AR, AD

ClinVar variants

P:48U:290B:377

Top phenotype

Osteogenesis imperfecta, type XIII

gnomAD constraint

pLI —, LoF o/e 0.3

Max pathogenic AF

—

Genomic locus

chr8:22,165,140-22,212,326

External References & Databases

Ensembl (ENSG00000168487)

Transcript & Mutation Effects

hg38 • Region Span ~47.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

osteogenesis imperfecta type 13STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013924

Submitter: PanelApp Australia

high bone mass osteogenesis imperfectaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017791

Submitter: Orphanet

osteogenesis imperfecta type 13MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013924

Submitter: Ambry Genetics

osteogenesis imperfecta type 3SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009804

Submitter: Orphanet

osteogenesis imperfecta type 13STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013924

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Osteogenesis imperfecta, type XIIIAR

Manifestation: Craniofacial; Musculoskeletal; 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: The use of bisphosphonates has been described, but it is unclear if an early (genetic) diagnosis would be advantageous

Refs: 22052668; 22482805

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BMP1 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 876

Inborn genetic diseasesTotal: 138

Osteogenesis imperfecta type 13Total: 85

not specifiedTotal: 79

BMP1-related disorderTotal: 40

Osteogenesis imperfectaTotal: 30

Osteogenesis imperfecta type IIITotal: 2

Cataract 4 multiple typesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006129.5. 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	363 clinvar	3 clinvar	369
missense	4 clinvar	4 clinvar	280 clinvar	10 clinvar	1 clinvar	299
nonsense	8 clinvar	5 clinvar	1 clinvar			14
start loss	3 clinvar					3
frameshift	8 clinvar	2 clinvar	1 clinvar			11
splice donor/acceptor (+/-2bp)	1 clinvar	13 clinvar	5 clinvar			19
Total	24	24	290	373	4	715

Highest pathogenic variant AF is 0.000015552061

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006129.5	RefSeq	NP_006120.1	20	MANE Select
ENST00000306385.10	Ensembl	ENSP00000305714.5	20	MANE Select
NM_001199.4	RefSeq	NP_001190.1	16	MANE Plus Clinical
ENST00000306349.13	Ensembl	ENSP00000306121.8	16	MANE Plus Clinical

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
bmp1a	Danio rerio	Structure: osteoblast Quality: cuboid abnormal

Gene / Model

Organism

Observed Phenotype

bmp1a

Danio rerio

Structure: osteoblast

Quality: cuboid

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Adipogenesis
Cardiac Progenitor Differentiation
Canonical and Non-Canonical TGF-B signaling
EDA Signalling in Hair Follicle Development
Crosslinking of collagen fibrils

Biological Process

skeletal system development
cartilage condensation
ossification
proteolysis
multicellular organism development

Molecular Function

metalloendopeptidase activity
serine-type endopeptidase activity
cytokine activity
calcium ion binding
protein binding

Cellular Component

extracellular region
extracellular space
Golgi apparatus
vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000306385
Coding exons: 20
Length: 47591
Individuals with no LoFs: 125712
Homozygous LoFs: 0
Heterozygous LoFs: 36
Defined: 125748
p: 0.000143

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.99	512	655	0.782	0.0000437	6505
Missense (PolyPhen)		136	226.14	0.60139		2117
Synonymous	-0.281	274	268	1.02	0.0000198	1862
Loss of Function	4.74	16	53.3	0.300	0.00000287	560

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00016	0.00015	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cleaves the C-terminal propeptides of procollagen I, II and III. Induces cartilage and bone formation. May participate in dorsoventral patterning during early development by cleaving chordin (CHRD). Responsible for the proteolytic activation of lysyl oxidase LOX.;
Disease: DISEASE: Osteogenesis imperfecta 13 (OI13) [MIM:614856]: An autosomal recessive form of osteogenesis imperfecta, a connective tissue disorder characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI13 is characterized by normal teeth, faint blue sclerae, severe growth deficiency, borderline osteoporosis, severe bone deformity, and recurrent fractures affecting both upper and lower limbs. {ECO:0000269|PubMed:22052668, ECO:0000269|PubMed:22482805, ECO:0000269|PubMed:25402547}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.475

Intolerance Scores

LoFtool: 0.687
RVIS EVS: -1.96
RVIS percentile EVS: 1.84

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.915

Gene Damage Prediction

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