BMP10

protein-coding

bone morphogenetic protein 10, the group of Bone morphogenetic proteins

Gene summary

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate the mature protein, which binds to the activin receptor-like kinase 1 (ALK1) and plays important roles in cardiovascular development including cardiomyocyte proliferation and regulation of heart size, closure of the ductus arteriosus, angiogenesis and ventricular trabeculation. [provided by RefSeq, Aug 2016]

MANE transcript

NM_014482.3

Inheritance

ClinVar variants

U:43B:8

Top phenotype

EBV-positive nodal T- and NK-cell lymphoma

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr2:68,860,909-68,871,397

External References & Databases

Ensembl (ENSG00000163217)

Transcript & Mutation Effects

hg38 • Region Span ~10.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pulmonary arterial hypertensionMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: PanelApp Australia

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*BMP10* was first reported in relation to autosomal dominant congenital heart disease in 2015 (Levet et al., PMID: 26056270). One unique missense variant has been reported in two related probands in one publication (PMIDs: 35737725). The gene-disease relationship is supported by expression evidence and a knockout mouse model that shows *Bmp9*-mutant mice injected with anti-Bmp10 antibodies display patent ductus arteriosus (PMIDs: 23715323, 26056270). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 09/11/2023 (SOP Version 9)

dilated cardiomyopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: PanelApp Australia

pulmonary arterial hypertensionLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: ClinGen

BMP10 was first reported in relation to autosomal dominant pulmonary arterial hypertension in 2019 (Eyries et al., PMID: 30578383). At least 5 variants (missense and nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data, including protein interaction, biochemical function, and tissue expression. Variants in this gene have been reported in at least 5 probands in 4 publications (PMIDs: 29843651, 33187088, 31661308, 30578383). The mechanism for disease is haploinsufficiency. The gene-disease association is supported by data demonstrating protein interaction, biochemical function and tissue expression (PMIDs: 17068149, 29789425, 31661308). In summary, BMP10 currently has limited evidence supporting a gene-disease relationship with autosomal dominant pulmonary arterial hypertension. This classification was approved by the ClinGen PH Gene Curation Expert Panel on 08/30/2022.

left ventricular noncompactionLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0018901

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BMP10 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 45

not providedTotal: 4

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

Bladder exstrophy-epispadias-cloacal exstrophy complexTotal: 1

Left ventricular noncompactionTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014482.3. 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						0
missense			42 clinvar	6 clinvar	1 clinvar	49
nonsense			1 clinvar	1 clinvar		2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	43	7	1	51

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014482.3	RefSeq	NP_055297.1	2	MANE Select
ENST00000295379.2	Ensembl	ENSP00000295379.1	2	MANE Select
ENST00000960265.1	Ensembl	ENSP00000630324.1	2	Standard
ENST00000960265.2	Ensembl	ENSP00000630324.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
bmp10	Danio rerio	Structure: endothelial cell Quality: increased amount abnormal

Gene / Model

Organism

Observed Phenotype

bmp10

Danio rerio

Structure: endothelial cell

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Heart Development
VEGFA-VEGFR2 Signaling Pathway
Signal Transduction
alk in cardiac myocytes
GPCR signaling-G alpha q

Biological Process

cell adhesion
adult heart development
regulation of signaling receptor activity
negative regulation of endothelial cell migration
positive regulation of cardiac muscle hypertrophy

Molecular Function

cytokine activity
transforming growth factor beta receptor binding
hormone activity
protein binding
growth factor activity

Cellular Component

extracellular region
extracellular space
cytoplasm
cell surface
Z disc

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000295379
Coding exons: 2
Length: 6037
Individuals with no LoFs: 125728
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125732
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.02	192	236	0.813	0.0000130	2815
Missense (PolyPhen)		50	93.418	0.53523		1118
Synonymous	-0.497	101	94.8	1.06	0.00000564	813
Loss of Function	2.96	1	12.1	0.0827	6.03e-7	161

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	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for maintaining the proliferative activity of embryonic cardiomyocytes by preventing premature activation of the negative cell cycle regulator CDKN1C/p57KIP and maintaining the required expression levels of cardiogenic factors such as MEF2C and NKX2-5. Acts as a ligand for ACVRL1/ALK1, BMPR1A/ALK3 and BMPR1B/ALK6, leading to activation of SMAD1, SMAD5 and SMAD8 transcription factors. Inhibits endothelial cell migration and growth. May reduce cell migration and cell matrix adhesion in breast cancer cell lines. {ECO:0000269|PubMed:16049014, ECO:0000269|PubMed:17068149, ECO:0000269|PubMed:20608934}.;

Recessive Scores

pRec: 0.221

Intolerance Scores

LoFtool: 0.0486
RVIS EVS: 0.09
RVIS percentile EVS: 60.47

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.310

Gene Damage Prediction

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