GeneBe

GDF9

protein-coding

growth differentiation factor 9, the group of Transforming growth factor beta superfamily

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 ovarian function. Reduced expression of this gene may be associated with polycystic ovary syndrome and mutations in this gene may be more common in mothers of dizygotic twins. [provided by RefSeq, Jul 2016]

MANE transcript

NM_005260.7

Inheritance

AD, AR

ClinVar variants

P:6U:82B:11

Top phenotype

Premature ovarian failure 14

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr5:132,861,181-132,866,884

External References & Databases

Ensembl (ENSG00000164404)NCBI Gene (2661)OMIM (601918)HGNC:4224GenCCUniProt (O60383)AlphaFoldClinVar (GDF9)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~5.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

premature ovarian failure 14LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0044777

Submitter: Ambry Genetics

premature ovarian failure 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044777

Submitter: Labcorp Genetics (formerly Invitae)

premature ovarian failure 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044777

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Premature ovarian failure 14AR

Manifestation: Endocrine

Intervention: Endocrine

Rationale: The condition has been described as manifesting with primary amenorrhea, and medical management (treatment with conjugated estrogens followed by progesterone replacement in the first 12 days of the month) has been reported as resulting in complete breast development and normal menstrual cycles

Comments: Heterozygous variants have also been described as potentially contributing to the phenotype

Refs: 27603904Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GDF9 variants in ClinVar

5 Conditions Cataloged
not specifiedTotal: 75
not providedTotal: 14
Premature ovarian failure 14Total: 10
GDF9-related disorderTotal: 4
Genetic non-acquired premature ovarian failureTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005260.7. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
5
clinvar
 7
missense
1
clinvar
2
clinvar
76
clinvar
5
clinvar
1
clinvar
 85
nonsense
1
clinvar
3
clinvar
 4
start loss
0
frameshift
2
clinvar
1
clinvar
 3
splice donor/acceptor (+/-2bp)
0
Total248210199

Highest pathogenic variant AF is 0.000076213655

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_005260.7RefSeqNP_005251.12MANE Select
ENST00000687138.1EnsemblENSP00000510441.12MANE Select
NM_001288824.4RefSeqNP_001275753.12Standard
NM_001288825.4RefSeqNP_001275754.12Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
gdf9Danio rerio

Structure: female organism

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Ovarian steroidogenesis - Homo sapiens (human)
  • Ovarian Infertility Genes
  • GPCR signaling-G alpha q
  • GPCR signaling-cholera toxin
  • GPCR signaling-pertussis toxin

Biological Process

  • oocyte growth
  • transforming growth factor beta receptor signaling pathway
  • female gamete generation
  • positive regulation of cell population proliferation
  • regulation of signaling receptor activity

Molecular Function

  • cytokine activity
  • transforming growth factor beta receptor binding
  • growth factor activity

Cellular Component

  • extracellular space
  • cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000378673
Coding exons
2
Length
5704
Individuals with no LoFs
125682
Homozygous LoFs
0
Heterozygous LoFs
66
Defined
125748
p
0.000262
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.5662592351.100.00001262961
Missense (PolyPhen)6465.7490.9734813
Synonymous-0.5729689.11.080.00000462902
Loss of Function1.051014.30.7017.73e-7190

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000250.00025rare
Latino/Admixed American0.000170.00017rare
Ashkenazi Jewish0.0000990.000099rare
East Asian00.0absent
Finnish0.0000920.000092rare
European (Non-Finnish)0.000370.00037rare
South Asian0.000130.00013rare
Other0.00110.0011notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Required for ovarian folliculogenesis. Promotes primordial follicle development. Stimulates granulosa cell proliferation. Promotes cell transition from G0/G1 to S and G2/M phases, through an increase of CCND1 and CCNE1 expression, and RB1 phosphorylation. It regulates STAR expression and cAMP-dependent progesterone release in granulosa and thecal cells. Attenuates the suppressive effects of activin A on STAR expression and progesterone production by increasing the expression of inhibin B. It suppresses FST and FSTL3 production in granulosa-lutein cells. {ECO:0000269|PubMed:12050262, ECO:0000269|PubMed:19366876, ECO:0000269|PubMed:20660033, ECO:0000269|PubMed:21632818, ECO:0000269|PubMed:21829661}.;
Disease
DISEASE: Note=Altered GDF9 function may be involved in ovarian disorders and contribute to the likelihood of dizygotic twinning. {ECO:0000269|PubMed:16954162}.; DISEASE: Premature ovarian failure 14 (POF14) [MIM:618014]: 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:16278619, ECO:0000269|PubMed:16645022, ECO:0000269|PubMed:16954162, ECO:0000269|PubMed:17156781, ECO:0000269|PubMed:17482612, ECO:0000269|PubMed:19438907, ECO:0000269|PubMed:29044499}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool
0.461
RVIS EVS
-0.02
RVIS percentile EVS
52.09

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Indispensability pred.
E
Indispensability score
0.546

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.