BMP4
protein-codingbone morphogenetic protein 4, 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 each subunit of the disulfide-linked homodimer. This protein regulates heart development and adipogenesis. Mutations in this gene are associated with orofacial cleft and microphthalmia in human patients. The encoded protein may also be involved in the pathology of multiple cardiovascular diseases and human cancers. [provided by RefSeq, Jul 2016]
- BMP2B
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~9.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0011936
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AD
Disease ID:MONDO:0010906
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011936
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0100613
Submitter: ClinGen
*BMP4* was first reported in relation to autosomal dominant BMP4-related ocular growth disorder in 2008 (Bakrania P et al., PMID:18252212). Affected individuals present with a variety of symptoms including microphthalmia and other ocular features, and syndromic symptoms such as brain and digit abnormalities. At least 12 unique variants, mostly nonsense and frameshift, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in *BMP4* have been reported in individuals with the following disease entities: syndromic microphthalmia (OMIM:607932), orofacial cleft (OMIM:600625), and in the literature renal dysplasia has also been asserted. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism between cases with ocular features. Therefore, all cases with ocular features, meaning some of the renal dysplasia reports and all of the syndromic microphthalmia reports, into one disease entity entitled BMP4-related ocular growth disorder. The mechanism for disease appears to be heterozygous loss of function causing a range of phenotypes via variable expressivity (PMID: 21340693). This gene-disease relationship is supported by several mouse models and expression studies. Mouse models showed that disruption of the *BMP4* gene result in craniofacial defects, cystic kidneys, anormal male accessory glands, defective lens morphology and digit abnormalities, such as polydactyly; all of these features are also observed in humans with loss-of-function variants in *BMP4* (PMIDs:9851982, 19229034, 9268572). Introduction of beads carrying BMP4 protein rescued the improper lens induction phenotype in one report (PMID:9851982). BMP4 was demonstrated by expression studies to be expressed in the relevant tissues to the phenotype: brain, eye and hand (PMID:18252212). Variants in this gene have been reported in at least 10 probands in 6 publications (PMIDs:30568244, 21340693, 3492645, 31120642, 18252212, 31053785). Variants in this gene segregated with disease in 8 additional family members. More unscorable evidence is available in the literature. In summary, there is definitive evidence to support the relationship between *BMP4* and autosomal dominant BMP4-related ocular growth disorder. 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 Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on the meeting date 20 February 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0011936
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0019636
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0019354
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0011936
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0010906
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011936
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011936
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Endocrine; Musculoskeletal; Neurologic; Renal; 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to BMP4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001202.6. 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 | 6 | 46 | 2 | 54 | ||
| missense | 2 | 2 | 162 | 25 | 191 | |
| nonsense | 2 | 5 | 1 | 8 | ||
| start loss | 1 | 1 | ||||
| frameshift | 3 | 11 | 4 | 18 | ||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 3 | |||
| Total | 7 | 19 | 176 | 71 | 2 | 275 |
Highest pathogenic variant AF is 0.0000018592636
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001193.2 | 2 | MANE Select | |
| Ensembl | ENSP00000245451.4 | 2 | MANE Select | |
| RefSeq | NP_001334841.1 | 4 | Standard | |
| RefSeq | NP_001334842.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| bmp4 | Danio rerio | Structure: epicardium Quality: hypoplastic 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)
- Basal cell carcinoma - Homo sapiens (human)
- Thyroid hormone signaling pathway - Homo sapiens (human)
- Hippo signaling pathway - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- activation of MAPKK activity
- osteoblast differentiation
- ureteric bud development
- branching involved in ureteric bud morphogenesis
Molecular Function
- cytokine activity
- transforming growth factor beta receptor binding
- protein binding
- growth factor activity
- heparin binding
Cellular Component
- extracellular region
- extracellular space
- endoplasmic reticulum lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000245451
- Coding exons
- 2
- Length
- 9026
- Individuals with no LoFs
- 125649
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125652
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.01 | 212 | 257 | 0.823 | 0.0000163 | 2663 |
| Missense (PolyPhen) | 58 | 97.654 | 0.59394 | 1064 | ||
| Synonymous | 0.176 | 98 | 100 | 0.978 | 0.00000563 | 843 |
| Loss of Function | 3.25 | 1 | 14.2 | 0.0703 | 9.38e-7 | 133 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Induces cartilage and bone formation. Also acts in mesoderm induction, tooth development, limb formation and fracture repair. Acts in concert with PTHLH/PTHRP to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction (By similarity). {ECO:0000250}.;
- Disease
- DISEASE: Non-syndromic orofacial cleft 11 (OFC11) [MIM:600625]: A birth defect consisting of cleft lips with or without cleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides and range in severity from a simple notch in the upper lip to a complete opening in the lip extending into the floor of the nostril and involving the upper gum. {ECO:0000269|PubMed:19249007}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.931
Intolerance Scores
- LoFtool
- 0.237
- RVIS EVS
- 0.33
- RVIS percentile EVS
- 73.27
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.983
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |