BMP4

Chr 14

bone morphogenetic protein 4

Also known as: BMP2B, BMP2B1, MCOPS6, OFC11, ZYME

NCBI Gene: 652 ENSG00000125378 UniProt: P12644

This protein is a secreted growth factor of the TGF-beta superfamily that regulates essential developmental processes including neurogenesis, vascular development, and tooth formation by binding to BMP receptors and activating SMAD transcription factors. Mutations cause autosomal dominant microphthalmia and orofacial clefts, affecting craniofacial and ocular development. The gene is highly constrained against loss-of-function variants (pLI 0.96, LOEUF 0.33), indicating that complete loss of protein function is likely incompatible with normal development.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.33

Clinical Summary— BMP4

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Gene-Disease Validity (ClinGen)

BMP4-related ocular growth disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

21 unique Pathogenic / Likely Pathogenic· 178 VUS of 304 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

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GeneReview available — BMP4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.33LOEUF

pLI 0.956

Z-score 3.25

OE 0.07 (0.02–0.33)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.01Z-score

OE missense 0.82 (0.73–0.92)

212 obs / 257.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.07 (0.02–0.33)

0≤0.351.4

Missense OE?0.82 (0.73–0.92)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 1 / 14.2Missense obs/exp: 212 / 257.5Syn Z: 0.18

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveBMP4-related microphthalmia with brain and digit anomaliesLOFAD

This gene — mechanism propensity

0.4289th %ile

GOF

0.2796th %ile

LOF

0.64top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 71% of P/LP variants are LoF · LOEUF 0.33 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

Literature Evidence

DNThe difference in resulting phenotypes between c. 130G>T, p.(Gly44Ter) and c.171dupC, p.(Glu58Argfs*17) may therefore reflect the ability of these truncated prodomains to form a complex with growth factor dimers and produce a dominant-negative effect.1

LOFHaploinsufficiency of BMP4 and OTX2 in the Foetus with an abnormal facial profile detected in the first trimester of pregnancy.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

304 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic12

VUS178

Likely Benign58

Benign19

Conflicting26

Pathogenic

Likely Pathogenic

178

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	2	2	0	9
Likely Pathogenic	10	2	0	0	12
VUS	7	153	13	5	178
Likely Benign	0	7	13	38	58
Benign	0	1	15	3	19
Conflicting	—				26
Total	22	165	43	46	302

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

16 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap BMP4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →