GeneBe

BMPR1A

protein-coding

bone morphogenetic protein receptor type 1A, the group of Type 1 receptor serine/threonine kinases|CD molecules

Gene summary

The bone morphogenetic protein (BMP) receptors are a family of transmembrane serine/threonine kinases that include the type I receptors BMPR1A and BMPR1B and the type II receptor BMPR2. These receptors are also closely related to the activin receptors, ACVR1 and ACVR2. The ligands of these receptors are members of the TGF-beta superfamily. TGF-betas and activins transduce their signals through the formation of heteromeric complexes with 2 different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Type II receptors bind ligands in the absence of type I receptors, but they require their respective type I receptors for signaling, whereas type I receptors require their respective type II receptors for ligand binding. [provided by RefSeq, Jul 2008]

Previous symbols:
  • ACVRLK3

MANE transcript

NM_004329.3

Inheritance

AD

ClinVar variants

P:317U:1271B:571

Top phenotype

Polyposis syndrome, hereditary mixed, 2; Polyposis, juvenile intestinal

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr10:86,755,786-86,932,825

External References & Databases

Ensembl (ENSG00000107779)NCBI Gene (657)OMIM (601299)HGNC:1076GenCCUniProt (P36894)AlphaFoldClinVar (BMPR1A)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~177.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart defects, multiple typesLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0000119

Submitter: Ambry Genetics

hereditary mixed polyposis syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011023

Submitter: Orphanet

juvenile polyposis syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017380

Submitter: ClinGen

BMPR1A was first reported in relation to Autosomal Dominant Juvenile Polyposis Syndrome (JPS) in 2001 (PMID 11381269). Juvenile Polyposis Syndrome is characterized by multiple gastrointestinal polyps and a predisposition to gastrointestinal cancer. A very small fraction of JPS patients (around 9%) have cardiovascular defects (PMID: 32398773). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) and inheritance pattern. Therefore, the following disease entities have been lumped into one disease entities, JPS (OMIM # 174900) and hereditary mixed polyposis syndrome-2 (HMPS2, OMIM # 610069). 17 variants (including missense, nonsense, and frameshift variants) reported in 17 probands in 5 publications (PMIDs: 15235019, 11381269, 11536076, 12136244, 17325551, 26171675) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Multiple gastrointestinal polyps are universally reported in JPS patients with BMPR1A variants, while the cancer risk is less clear. Colon cancer, and other cancer types, have been observed in BMPR1A carriers with JPS and one study reported that cancer was observed in 8.5% of JPS patients (PMID: 32398773). LOH has been studied in some occasions, with LOH reported in around half of polyps from BMPR1A variant carriers (PMID: 26171675). The mechanism of pathogenicity appears to be LOF. This gene-disease association is also supported by animal models and in vitro functional reporter assays (5 points). Reporter assays in cell lines (non-patient) indicated that multiple missense variants, previously reported in patients, decreased membrane localization of the resulting gene product (PMID: 23433720). While complete null mice are embryonic lethal, multiple murine models of (intestinal specific) conditional BMPR1A deletion showed intestinal hyperplasia and gastrointestinal polyps. A variety of gastrointestinal specific BMPR1A conditional mouse models also develop phenotypes consistent with JPS, specifically multiple gastrointestinal polyps (PMIDs: 26773796, 27856416, 15378062). In summary, BMPR1A is definitively associated with Autosomal Dominant Juvenile Polyposis Syndrome.

primary ovarian failureMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005387

Submitter: PanelApp Australia

juvenile polyposis syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0017380

Submitter: Labcorp Genetics (formerly Invitae)

pulmonary arterial hypertensionNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0015924

Submitter: ClinGen

After a comprehensive literature review, the gene-disease relationship between BMPR1A and pulmonary arterial hypertension is disputed. Despite experimental evidence including function in biochemical pathways, protein interaction with BMPR2, and expression evidence in pulmonary artery smooth muscle cells, there is insufficient proband level genetic evidence to classify the relationship as limited. Instead, a classification of disputed was reached due to insufficient proband level evidence over multiple years. Classification approved by Pulmonary Hypertension GCEP panal on 8/30/22.

polyposis syndrome, hereditary mixed, 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012405

Submitter: Genomics England PanelApp

juvenile polyposis syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0017380

Submitter: PanelApp Australia

generalized juvenile polyposis/juvenile polyposis coliSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008276

Submitter: Genomics England PanelApp

juvenile polyposis syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017380

Submitter: G2P

generalized juvenile polyposis/juvenile polyposis coliDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008276

Submitter: Ambry Genetics

generalized juvenile polyposis/juvenile polyposis coliSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008276

Submitter: Orphanet

Clinical Genomic Database (CGD)

Polyposis syndrome, hereditary mixed, 2; Polyposis, juvenile intestinalAD

Manifestation: Oncologic

Intervention: Oncologic

Rationale: Surveillance (eg, with colonoscopy and endoscopic polypectomy, as well upper endoscopy for symptomatic individuals, and monitoring for sequelae including anemia and rectal bleeding) may be beneficial, though partial/total colectomy/gastrectomy may be indicated in some individuals with a large polyp burden; Indivduals may have a variety of HHT-related vascular complications, including arteriovenous malformations, aortic dilatation, and bleeding diatheses, and surveillance and early intervention related to manifestations (eg, related to thromboembolism or hepatic disease) may decrease morbidity and mortality

Refs: 5483654; 4544011; 7059958; 3707330; 8037173; 7582207; 11381269; 12136244; 15235019; 16152648; 16525031; 17873119; 20843829; 22171123; 22810475Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BMPR1A variants in ClinVar

26 Conditions Cataloged
Juvenile polyposis syndromeTotal: 1921
Hereditary cancer-predisposing syndromeTotal: 1709
not providedTotal: 398
not specifiedTotal: 226
Polyposis syndrome, hereditary mixed, 2Total: 197
Generalized juvenile polyposis/juvenile polyposis coliTotal: 61
Pulmonary arterial hypertensionTotal: 53
BMPR1A-related disorderTotal: 46

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004329.3. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
2
clinvar
473
clinvar
43
clinvar
 519
missense
1
clinvar
31
clinvar
1219
clinvar
54
clinvar
1
clinvar
 1306
nonsense
64
clinvar
12
clinvar
2
clinvar
 78
start loss
3
clinvar
3
clinvar
 6
frameshift
136
clinvar
18
clinvar
40
clinvar
 194
splice donor/acceptor (+/-2bp)
5
clinvar
43
clinvar
8
clinvar
 56
Total2091081271527442159

Highest pathogenic variant AF is 0.0000065731524

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 123 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_004329.3RefSeqNP_004320.211MANE Select
ENST00000372037.8EnsemblENSP00000361107.211MANE Select
NM_001406559.1RefSeqNP_001393488.112Standard
NM_001406560.1RefSeqNP_001393489.112Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
bmpr1abDanio rerio

Structure: whole organism

Quality: wholly dorsalized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • TGF-beta signaling pathway - Homo sapiens (human)
  • Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
  • Hippo signaling pathway - Homo sapiens (human)
  • Fluid shear stress and atherosclerosis - Homo sapiens (human)
  • Cytokine-cytokine receptor interaction - Homo sapiens (human)

Biological Process

  • in utero embryonic development
  • mesoderm formation
  • somitogenesis
  • Mullerian duct regression
  • positive regulation of mesenchymal cell proliferation

Molecular Function

  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • protein serine/threonine kinase activity
  • transmembrane receptor protein serine/threonine kinase activity
  • transforming growth factor beta-activated receptor activity
  • transforming growth factor beta receptor activity, type I

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • caveola
  • external side of plasma membrane
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000372037
Coding exons
11
Length
176189
Individuals with no LoFs
125741
Homozygous LoFs
0
Heterozygous LoFs
7
Defined
125748
p
0.0000278
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.922062990.6880.00001763487
Missense (PolyPhen)63118.430.531951380
Synonymous0.2731011050.9660.000005801002
Loss of Function4.19529.60.1690.00000162351

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000630.000062rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.0000180.000018rare
South Asian0.0000330.000033rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for BMP2, BMP4, GDF5 and GDF6. Positively regulates chondrocyte differentiation through GDF5 interaction. Mediates induction of adipogenesis by GDF6. {ECO:0000250|UniProtKB:P36895}.;
Disease
DISEASE: Polyposis syndrome, mixed hereditary 2 (HMPS2) [MIM:610069]: A disease is characterized by atypical juvenile polyps, colonic adenomas, and colorectal carcinomas. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A microdeletion of chromosome 10q23 involving BMPR1A and PTEN is a cause of chromosome 10q23 deletion syndrome, which shows overlapping features of the following three disorders: Bannayan-Zonana syndrome, Cowden disease and juvenile polyposis syndrome. {ECO:0000269|PubMed:11381269, ECO:0000269|PubMed:16525031}.;

Recessive Scores

pRec
0.539

Intolerance Scores

LoFtool
0.160
RVIS EVS
-0.4
RVIS percentile EVS
26.53

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.999

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerMediumMediumMedium
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