BMP6

protein-coding

bone morphogenetic protein 6, 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 a wide range of biological processes including iron homeostasis, fat and bone development, and ovulation. Differential expression of this gene may be associated with progression of breast and prostate cancer. Mutations in this gene may be associated with iron overload in human patients. [provided by RefSeq, Jul 2016]

Previous symbols:

MANE transcript

NM_001718.6

Inheritance

AD, AR

ClinVar variants

P:1U:99B:25

Top phenotype

Iron overload, susceptibility to

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr6:7,726,099-7,881,728

External References & Databases

Ensembl (ENSG00000153162)

Transcript & Mutation Effects

hg38 • Region Span ~155.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

iron overload, susceptibility toMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859316

Submitter: PanelApp Australia

iron overload, susceptibility toLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0859316

Submitter: ClinGen

The *BMP6* gene was first reported in relation to susceptibility to iron overload in 2006 (Babitt JL et al., PMID: 19252488), showing that BMP6 upregulates hepatocyte hepcidin expression—a process enhanced by hemojuvelin and blunted in* Hfe2*−/− hepatocytes. Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern.Six missense variants, with at least six probands reported in association with iron overload across six publications (PMID: 26582087, PMID: 28335084, PMID: 29695288, PMID: 27590690, PMID: 34037557, PMID: 38719717), were evaluated but not included due to high allele frequency in healthy populations (gnomAD v4.1).One missense variant, c.1180G>A (p.Val394Met), with additional in vitro assay data showing a three-fold reduction in hepcidin induction by the mutant compared to wild-type BMP6, was included in this curation (PMID: 34037557). The mechanism of pathogenicity appears to be loss of function.This gene-disease relationship is also supported by animal models showing accumulation of iron in the liver, the acinar cells of the exocrine pancreas, the heart, and the renal convoluted tubules (PMID: 19252488; PMID: 19252486), as well as expression studies showing *Bmp6 *expression induced by dietary iron content (PMID: 18539898). In summary, there is limited evidence supporting the relationship between *BMP6* and susceptibility to iron overload. This classification was approved by the ClinGen IEM GCEP at the meeting on May 9, 2025 (SOP Version 11).

Clinical Genomic Database (CGD)

Iron overload, susceptibility toAD/AR

Manifestation: Gastrointestinal

Intervention: Gastrointestinal

Rationale: The condition may involve increased risk of liver dysfunction, and awareness may allow preventative measures such as avoidance of other risk factors for hepatic dysfunction

Refs: 26582087; 28335084; 32464486

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BMP6 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 92

BMP6-related disorderTotal: 21

not providedTotal: 11

Iron overload, susceptibility toTotal: 9

Premature ovarian failureTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001718.6. 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			1 clinvar	11 clinvar	4 clinvar	16
missense		1 clinvar	95 clinvar	8 clinvar	2 clinvar	106
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	1	99	19	6	125

Highest pathogenic variant AF is 0.000019206682

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001718.6	RefSeq	NP_001709.1	7	MANE Select
ENST00000283147.7	Ensembl	ENSP00000283147.6	7	MANE Select
ENST00000946083.1	Ensembl	ENSP00000616142.1	7	Standard
ENST00000946083.2	Ensembl	ENSP00000616142.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

TGF-beta signaling pathway - Homo sapiens (human)
Hippo signaling pathway - Homo sapiens (human)
Ovarian steroidogenesis - Homo sapiens (human)
TGF-Core
Vitamin D Receptor Pathway

Biological Process

negative regulation of transcription by RNA polymerase II
skeletal system development
osteoblast differentiation
eye development
kidney development

Molecular Function

cytokine activity
transforming growth factor beta receptor binding
growth factor activity
protein heterodimerization activity
BMP receptor binding

Cellular Component

extracellular space
cytoplasm
vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000283147
Coding exons: 7
Length: 154626
Individuals with no LoFs: 125744
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125748
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.03	315	268	1.18	0.0000153	3306
Missense (PolyPhen)		130	128.12	1.0147		1444
Synonymous	-0.660	120	111	1.08	0.00000657	1020
Loss of Function	3.59	4	22.3	0.180	0.00000122	239

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Induces cartilage and bone formation.;

Recessive Scores

pRec: 0.373

Intolerance Scores

LoFtool: 0.0702
RVIS EVS: -0.34
RVIS percentile EVS: 30.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.936

Gene Damage Prediction

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