GDF9

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

Basic information

Region (hg38): 5:132861181-132866884

Links

ENSG00000164404 ∙ NCBI:2661 ∙ OMIM:601918 ∙ HGNC:4224 ∙ Uniprot:O60383 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• premature ovarian failure 14 (Limited), mode of inheritance: AD
• premature ovarian failure 14 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Premature ovarian failure 14	AR	Endocrine	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	Endocrine	27603904
Heterozygous variants have also been described as potentially contributing to the phenotype

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GDF9 gene.

• not_specified (66 variants)
• not_provided (11 variants)
• Premature_ovarian_failure_14 (8 variants)
• GDF9-related_disorder (3 variants)
• Genetic_non-acquired_premature_ovarian_failure (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GDF9 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000005260.7. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	3		4
missense	1	1	69	4	1	76
nonsense	1		2			3
start loss						0
frameshift		2				2
splice donor/acceptor (+/-2bp)						0
Total	2	3	72	7	1

Highest pathogenic variant AF is 0.0000762137

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GDF9	protein_coding	protein_coding	ENST00000378673	2	5704

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000552	0.688	125682	0	66	125748	0.000262

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.566	259	235	1.10	0.0000126	2961
Missense in Polyphen		64	65.749	0.9734		813
Synonymous	-0.572	96	89.1	1.08	0.00000462	902
Loss of Function	1.05	10	14.3	0.701	7.73e-7	190

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000420	0.000420
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.00	0.00
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000369	0.000369
Middle Eastern	0.00	0.00
South Asian	0.000131	0.000131
Other	0.00114	0.00114

dbNSFP

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.
• Pathway: Ovarian steroidogenesis - Homo sapiens (human);Ovarian Infertility Genes;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;TGF-beta super family signaling pathway canonical;GPCR signaling-G alpha s Epac and ERK;GPCR signaling-G alpha s PKA and ERK;GPCR signaling-G alpha i;BMP2 signaling TGF-beta MV;BMP signaling Dro (Consensus)

Intolerance Scores

• loftool: 0.461
• rvis_EVS: -0.02
• rvis_percentile_EVS: 52.09

Haploinsufficiency Scores

• pHI: 0.126
• hipred: N
• hipred_score: 0.182
• ghis: 0.486

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.546

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gdf9
• Phenotype: endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; reproductive system phenotype

Zebrafish Information Network

• Gene name: gdf9
• Affected structure: female organism
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• 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;positive regulation of pathway-restricted SMAD protein phosphorylation;negative regulation of cell growth;BMP signaling pathway;regulation of apoptotic process;regulation of MAPK cascade;cell development;SMAD protein signal transduction;regulation of progesterone secretion
• Cellular component: extracellular space;cytoplasm
• Molecular function: cytokine activity;transforming growth factor beta receptor binding;growth factor activity