BMP4

bone morphogenetic protein 4, the group of Bone morphogenetic proteins

Basic information

Region (hg38): 14:53949735-53958761

Previous symbols: [ "BMP2B" ]

Links

ENSG00000125378 ∙ NCBI:652 ∙ OMIM:112262 ∙ HGNC:1071 ∙ Uniprot:P12644 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• microphthalmia with brain and digit anomalies (Definitive), mode of inheritance: AD
• Stickler syndrome (Moderate), mode of inheritance: AR
• microphthalmia with brain and digit anomalies (Strong), mode of inheritance: AD
• microphthalmia with brain and digit anomalies (Moderate), mode of inheritance: AD
• microphthalmia with brain and digit anomalies (Moderate), mode of inheritance: AD
• renal agenesis, unilateral (Supportive), mode of inheritance: AD
• microphthalmia with brain and digit anomalies (Strong), mode of inheritance: AD
• orofacial cleft 11 (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Microphthalmia, syndromic 6; Orofacial cleft 11	AD	General	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	Craniofacial; Endocrine; Musculoskeletal; Neurologic; Renal; Ophthalmologic	18252212; 18305125; 19249007; 21340693

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the BMP4 gene.

• Microphthalmia with brain and digit anomalies;Orofacial cleft 11 (49 variants)
• not provided (48 variants)
• Orofacial cleft 11;Microphthalmia with brain and digit anomalies (42 variants)
• Orofacial cleft 11 (34 variants)
• Microphthalmia with brain and digit anomalies (25 variants)
• Cleft Lip +/- Cleft Palate, Autosomal Dominant (19 variants)
• Syndromic Microphthalmia, Dominant (17 variants)
• Inborn genetic diseases (16 variants)
• Orofacial cleft (12 variants)
• not specified (9 variants)
• BMP4-Related Syndromic Microphthalmia (9 variants)
• BMP4-related condition (5 variants)
• See cases (1 variants)
• Kapur-Toriello syndrome (1 variants)
• Irido-corneo-trabecular dysgenesis (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the BMP4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	20	2	25
missense		1	64	6	1	72
nonsense	2	2	2			6
start loss						0
frameshift	1	1	2			4
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region			2			2
non coding			13	9	8	30
Total	3	4	85	35	11

Variants in BMP4

This is a list of pathogenic ClinVar variants found in the BMP4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
14-53949760-T-C		Orofacial cleft 11 • Syndromic Microphthalmia, Dominant • Cleft Lip +/- Cleft Palate, Autosomal Dominant	Uncertain significance (Jan 12, 2018)
14-53949778-T-A		Orofacial cleft 11	Uncertain significance (Jan 12, 2018)
14-53949781-G-A		Orofacial cleft 11 • Microphthalmia with brain and digit anomalies • Orofacial cleft	Conflicting classifications of pathogenicity (Jan 13, 2018)
14-53949881-TC-T		Cleft Lip +/- Cleft Palate, Autosomal Dominant • Orofacial cleft • Syndromic Microphthalmia, Dominant • BMP4-Related Syndromic Microphthalmia	Uncertain significance (Jun 14, 2016)
14-53949882-CCT-C		Syndromic Microphthalmia, Dominant • Orofacial cleft • Cleft Lip +/- Cleft Palate, Autosomal Dominant • BMP4-Related Syndromic Microphthalmia	Conflicting classifications of pathogenicity (Aug 18, 2019)
14-53949882-CCTTTT-C		Syndromic Microphthalmia, Dominant • Orofacial cleft • Cleft Lip +/- Cleft Palate, Autosomal Dominant • BMP4-Related Syndromic Microphthalmia	Uncertain significance (Jun 14, 2016)
14-53949883-C-T		Syndromic Microphthalmia, Dominant • Orofacial cleft • Orofacial cleft 11	Conflicting classifications of pathogenicity (Aug 01, 2022)
14-53949883-CT-C			Likely benign (Sep 06, 2019)
14-53949883-C-CA		Orofacial cleft • Cleft Lip +/- Cleft Palate, Autosomal Dominant • Syndromic Microphthalmia, Dominant • BMP4-Related Syndromic Microphthalmia	Conflicting classifications of pathogenicity (Aug 21, 2019)
14-53949884-T-A		Cleft Lip +/- Cleft Palate, Autosomal Dominant • Orofacial cleft 11 • Microphthalmia with brain and digit anomalies	Benign/Likely benign (Jan 12, 2018)
14-53949883-C-CAT		Syndromic Microphthalmia, Dominant • Cleft Lip +/- Cleft Palate, Autosomal Dominant • Orofacial cleft • BMP4-Related Syndromic Microphthalmia	Conflicting classifications of pathogenicity (Aug 15, 2019)
14-53949883-C-CCT		BMP4-Related Syndromic Microphthalmia • Orofacial cleft • Syndromic Microphthalmia, Dominant • Cleft Lip +/- Cleft Palate, Autosomal Dominant	Uncertain significance (Jun 14, 2016)
14-53949883-C-CTT			Benign (Apr 01, 2022)
14-53949883-C-CATT		Orofacial cleft • Cleft Lip +/- Cleft Palate, Autosomal Dominant • BMP4-Related Syndromic Microphthalmia • Syndromic Microphthalmia, Dominant	Conflicting classifications of pathogenicity (Aug 15, 2019)
14-53949883-C-CTTT		Cleft Lip +/- Cleft Palate, Autosomal Dominant • BMP4-Related Syndromic Microphthalmia • Orofacial cleft • Syndromic Microphthalmia, Dominant	Conflicting classifications of pathogenicity (Sep 02, 2019)
14-53949889-T-A		Syndromic Microphthalmia, Dominant • Orofacial cleft 11 • Cleft Lip +/- Cleft Palate, Autosomal Dominant	Uncertain significance (Jan 12, 2018)
14-53949901-T-A		Cleft Lip +/- Cleft Palate, Autosomal Dominant • Orofacial cleft 11 • Syndromic Microphthalmia, Dominant	Uncertain significance (Jan 13, 2018)
14-53949944-G-A		Orofacial cleft 11 • Cleft Lip +/- Cleft Palate, Autosomal Dominant • Microphthalmia with brain and digit anomalies	Benign/Likely benign (Sep 02, 2019)
14-53949997-G-C		Syndromic Microphthalmia, Dominant • Cleft Lip +/- Cleft Palate, Autosomal Dominant • Orofacial cleft 11	Uncertain significance (Jan 12, 2018)
14-53950001-A-T		Orofacial cleft 11 • Microphthalmia with brain and digit anomalies	Conflicting classifications of pathogenicity (Jan 13, 2018)
14-53950004-T-A		Orofacial cleft 11 • Microphthalmia with brain and digit anomalies	Benign/Likely benign (Jan 13, 2018)
14-53950036-C-T		Microphthalmia with brain and digit anomalies;Orofacial cleft 11 • Inborn genetic diseases	Uncertain significance (Jul 20, 2022)
14-53950050-C-T		Microphthalmia with brain and digit anomalies;Orofacial cleft 11	Likely benign (Jul 09, 2022)
14-53950080-T-C		Orofacial cleft 11;Microphthalmia with brain and digit anomalies	Likely benign (Dec 02, 2021)
14-53950083-C-T		BMP4-related disorder	Likely benign (Jan 15, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
BMP4	protein_coding	protein_coding	ENST00000245451	2	9026

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.956	0.0436	125649	0	3	125652	0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.01	212	257	0.823	0.0000163	2663
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000622	0.0000617
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000882	0.00000880
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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);Fluid shear stress and atherosclerosis - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);TGF-Core;Heart Development;Neural Crest Differentiation;Adipogenesis;Cardiac Progenitor Differentiation;Hair Follicle Development- Induction (Part 1 of 3);Differentiation Pathway;Mesodermal Commitment Pathway;Ectoderm Differentiation;Differentiation of white and brown adipocyte;BMP Signaling Pathway in Eyelid Development;ESC Pluripotency Pathways;TGF-beta Receptor Signaling;alk in cardiac myocytes;Post-translational protein phosphorylation;Post-translational protein modification;Metabolism of proteins;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Extracellular matrix organization;Molecules associated with elastic fibres;Elastic fibre formation;TGF-beta super family signaling pathway canonical;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs);GPCR signaling-G alpha s Epac and ERK;GPCR signaling-G alpha s PKA and ERK;BMP receptor signaling;GPCR signaling-G alpha i;BMP2 signaling TGF-beta MV;BMP signaling Dro (Consensus)

Recessive Scores

• pRec: 0.931

Intolerance Scores

• loftool: 0.237
• rvis_EVS: 0.33
• rvis_percentile_EVS: 73.27

Haploinsufficiency Scores

• pHI: 0.992
• hipred: Y
• hipred_score: 0.875
• ghis: 0.475

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.983

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Bmp4
• Phenotype: endocrine/exocrine gland phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; craniofacial phenotype; muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype; liver/biliary system phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; reproductive system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); vision/eye phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hearing/vestibular/ear phenotype; digestive/alimentary phenotype; renal/urinary system phenotype; skeleton phenotype

Zebrafish Information Network

• Gene name: bmp4
• Affected structure: epicardium
• Phenotype tag: abnormal
• Phenotype quality: hypoplastic

Gene ontology

• 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;kidney development;mesonephros development;neural tube closure;positive regulation of protein phosphorylation;positive regulation of endothelial cell proliferation;endochondral ossification;blood vessel endothelial cell proliferation involved in sprouting angiogenesis;chondrocyte differentiation;hematopoietic progenitor cell differentiation;lymphoid progenitor cell differentiation;renal system process;BMP signaling pathway involved in heart induction;secondary heart field specification;outflow tract septum morphogenesis;membranous septum morphogenesis;muscular septum morphogenesis;aortic valve morphogenesis;pulmonary valve morphogenesis;endocardial cushion development;epithelial to mesenchymal transition involved in endocardial cushion formation;cardiac right ventricle morphogenesis;apoptotic process involved in endocardial cushion morphogenesis;cardiac septum development;type B pancreatic cell development;mesenchymal to epithelial transition involved in metanephros morphogenesis;common-partner SMAD protein phosphorylation;smoothened signaling pathway;germ cell development;endoderm development;mesodermal cell fate determination;positive regulation of cell population proliferation;negative regulation of cell population proliferation;post-embryonic development;anterior/posterior axis specification;specification of animal organ position;regulation of cell fate commitment;regulation of signaling receptor activity;positive regulation of endothelial cell migration;positive regulation of gene expression;negative regulation of gene expression;positive regulation of epithelial to mesenchymal transition;positive regulation of pathway-restricted SMAD protein phosphorylation;positive regulation of cell death;telencephalon development;dorsal/ventral neural tube patterning;telencephalon regionalization;pituitary gland development;erythrocyte differentiation;monocyte differentiation;macrophage differentiation;positive regulation of bone mineralization;BMP signaling pathway;positive regulation of BMP signaling pathway;positive regulation of protein binding;negative regulation of chondrocyte differentiation;positive regulation of collagen biosynthetic process;negative regulation of T cell differentiation in thymus;negative regulation of immature T cell proliferation in thymus;protein localization to nucleus;embryonic hindlimb morphogenesis;tendon cell differentiation;deltoid tuberosity development;regulation of protein import into nucleus;negative regulation of phosphorylation;odontogenesis of dentin-containing tooth;odontogenesis;regulation of odontogenesis of dentin-containing tooth;embryonic digit morphogenesis;regulation of apoptotic process;positive regulation of apoptotic process;negative regulation of apoptotic process;steroid hormone mediated signaling pathway;negative regulation of MAP kinase activity;regulation of MAPK cascade;post-translational protein modification;cellular protein metabolic process;positive regulation of endothelial cell differentiation;positive regulation of epidermal cell differentiation;negative regulation of myoblast differentiation;positive regulation of neuron differentiation;positive regulation of osteoblast differentiation;positive regulation of ossification;negative regulation of cell cycle;negative regulation of mitotic nuclear division;negative regulation of striated muscle tissue development;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;lung alveolus development;intermediate mesodermal cell differentiation;cell development;positive regulation of smooth muscle cell proliferation;neuron fate commitment;embryonic cranial skeleton morphogenesis;smooth muscle tissue development;branching morphogenesis of an epithelial tube;positive regulation of epithelial cell proliferation;negative regulation of epithelial cell proliferation;positive chemotaxis;regulation of smooth muscle cell differentiation;cardiac muscle cell differentiation;positive regulation of cardiac muscle fiber development;inner ear receptor cell differentiation;cloacal septation;lens induction in camera-type eye;embryonic skeletal joint morphogenesis;cranial suture morphogenesis;positive regulation of SMAD protein signal transduction;regulation of pathway-restricted SMAD protein phosphorylation;SMAD protein signal transduction;lung morphogenesis;bronchus development;trachea development;trachea formation;epithelial tube branching involved in lung morphogenesis;branching involved in prostate gland morphogenesis;bud elongation involved in lung branching;epithelial cell proliferation involved in lung morphogenesis;bud dilation involved in lung branching;negative regulation of cell death;mammary gland formation;epithelial-mesenchymal cell signaling;negative regulation of prostatic bud formation;regulation of branching involved in prostate gland morphogenesis;coronary vasculature development;positive regulation of cartilage development;positive regulation of branching involved in lung morphogenesis;BMP signaling pathway involved in ureter morphogenesis;BMP signaling pathway involved in renal system segmentation;pulmonary artery endothelial tube morphogenesis;BMP signaling pathway involved in heart development;pharyngeal arch artery morphogenesis;negative regulation of thymocyte apoptotic process;positive regulation of ERK1 and ERK2 cascade;cellular response to BMP stimulus;BMP signaling pathway involved in nephric duct formation;renal system development;glomerular visceral epithelial cell development;negative regulation of branch elongation involved in ureteric bud branching by BMP signaling pathway;specification of ureteric bud anterior/posterior symmetry by BMP signaling pathway;glomerular capillary formation;negative regulation of glomerular mesangial cell proliferation;mesenchymal cell proliferation involved in ureteric bud development;mesenchymal cell differentiation involved in kidney development;ureter epithelial cell differentiation;ureter smooth muscle cell differentiation;mesenchymal cell proliferation involved in ureter development;negative regulation of mesenchymal cell proliferation involved in ureter development;metanephric collecting duct development;positive regulation of kidney development;negative regulation of branching involved in ureteric bud morphogenesis;negative regulation of glomerulus development;positive regulation of cell proliferation involved in outflow tract morphogenesis;regulation of pri-miRNA transcription by RNA polymerase II;negative regulation of pri-miRNA transcription by RNA polymerase II;positive regulation of production of miRNAs involved in gene silencing by miRNA;cardiac jelly development;positive regulation of cardiac neural crest cell migration involved in outflow tract morphogenesis;negative regulation of metanephric S-shaped body morphogenesis;negative regulation of metanephric comma-shaped body morphogenesis;negative regulation of cell proliferation involved in heart morphogenesis;negative regulation of extrinsic apoptotic signaling pathway
• Cellular component: extracellular region;extracellular space;endoplasmic reticulum lumen
• Molecular function: cytokine activity;transforming growth factor beta receptor binding;protein binding;growth factor activity;heparin binding;co-receptor binding;chemoattractant activity;BMP receptor binding