BMP4

Chr 14AD

bone morphogenetic protein 4

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

NCBI Gene: 652 ENSG00000125378 UniProt: P12644

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]

Primary Disease Associations & Inheritance

Microphthalmia, syndromic 6MIM #607932

Orofacial cleft 11MIM #600625

UniProtNon-syndromic orofacial cleft 11

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

1.0

Missense Z

0.33

LOEUF· LoF intolerant

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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Clinical Trials

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

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

1.01Z-score

OE missense 0.82 (0.73–0.92)

212 obs / 257.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.07 (0.02–0.33)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.73–0.92)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98

0≤1.21.6

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

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 · LOEUF 0.33

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.PMID:30568244

LOFHaploinsufficiency of BMP4 and OTX2 in the Foetus with an abnormal facial profile detected in the first trimester of pregnancy.PMID:29299063

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