BMP15

protein-coding

bone morphogenetic protein 15, 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 subunits of a disulfide-linked homodimer, or alternatively, a heterodimer, with the related protein, growth differentiation factor 9 (GDF9). This protein plays a role in oocyte maturation and follicular development, through activation of granulosa cells. Defects in this gene are the cause of ovarian dysgenesis and are associated with premature ovarian failure. [provided by RefSeq, Aug 2016]

MANE transcript

NM_005448.2

Inheritance

AD, XL

ClinVar variants

P:12U:53B:17

Top phenotype

Ovarian dysgenesis 2

gnomAD constraint

pLI —, LoF o/e 0.68

Max pathogenic AF

—

Genomic locus

chrX:50,910,735-50,916,641

External References & Databases

Ensembl (ENSG00000130385)

Transcript & Mutation Effects

hg38 • Region Span ~5.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ovarian dysgenesis 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0010349

Submitter: Ambry Genetics

ovarian dysgenesis 2MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010349

Submitter: Ambry Genetics

46 XX gonadal dysgenesisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009299

Submitter: Orphanet

ovarian dysgenesis 2STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010349

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Ovarian dysgenesis 2XL

Manifestation: Endocrine; Genitourinary; Obstetric

Intervention: Obstetric

Rationale: Genetic knowledge may allow reproductive capabilities such as via egg preservation

Refs: 15136966; 16508750; 19263482

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BMP15 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 41

Ovarian dysgenesis 2Total: 25

not providedTotal: 18

BMP15-related disorderTotal: 6

not specifiedTotal: 6

Premature ovarian failure 4Total: 4

Genetic non-acquired premature ovarian failureTotal: 2

Hereditary pancreatitisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005448.2. 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				4 clinvar	1 clinvar	5
missense	5 clinvar	3 clinvar	52 clinvar	11 clinvar	1 clinvar	72
nonsense	2 clinvar	1 clinvar				3
start loss						0
frameshift		1 clinvar	1 clinvar			2
splice donor/acceptor (+/-2bp)						0
Total	7	5	53	15	2	82

Highest pathogenic variant AF is 0.00019167423

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005448.2	RefSeq	NP_005439.2	2	MANE Select
ENST00000252677.4	Ensembl	ENSP00000252677.3	2	MANE Select

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
bmp15	Danio rerio	Structure: ovarian follicle Quality: maturity abnormal

Gene / Model

Organism

Observed Phenotype

bmp15

Danio rerio

Structure: ovarian follicle

Quality: maturity

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ovarian steroidogenesis - Homo sapiens (human)
TGF-Core
Post-translational protein phosphorylation
Post-translational protein modification
Metabolism of proteins

Biological Process

ovarian follicle development
female gamete generation
regulation of signaling receptor activity
positive regulation of pathway-restricted SMAD protein phosphorylation
BMP signaling pathway

Molecular Function

cytokine activity
transforming growth factor beta receptor binding
growth factor activity

Cellular Component

extracellular space
endoplasmic reticulum lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000252677
Coding exons: 2
Length: 5824
Individuals with no LoFs: 125707
Homozygous LoFs: 4
Heterozygous LoFs: 11
Defined: 125722
p: 0.0000597

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0699	157	159	0.984	0.0000127	2547
Missense (PolyPhen)		34	36.963	0.91984		606
Synonymous	0.0609	56	56.6	0.990	0.00000405	794
Loss of Function	0.948	7	10.3	0.681	8.83e-7	143

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00015	0.00012	rare
Latino/Admixed American	0.000036	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00014	0.000097	rare
South Asian	0.000052	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in follicular development. Oocyte- specific growth/differentiation factor that stimulates folliculogenesis and granulosa cell (GC) growth. {ECO:0000269|PubMed:18227435}.;
Disease: DISEASE: Ovarian dysgenesis 2 (ODG2) [MIM:300510]: A disorder characterized by lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism as a result of streak gonads. {ECO:0000269|PubMed:15136966}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Premature ovarian failure 4 (POF4) [MIM:300510]: An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. {ECO:0000269|PubMed:16464940, ECO:0000269|PubMed:16508750, ECO:0000269|PubMed:16645022, ECO:0000269|PubMed:19263482, ECO:0000269|PubMed:19438907}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.191

Intolerance Scores

LoFtool: 0.215
RVIS EVS: 0.6
RVIS percentile EVS: 82.66

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.223

Gene Damage Prediction

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