GDF9

Chr 5AR

growth differentiation factor 9

Also known as: POF14

NCBI Gene: 2661 ENSG00000164404 UniProt: O60383 OMIM: 601918

This gene encodes a secreted ligand of the TGF-beta superfamily that is required for ovarian folliculogenesis, promoting primordial follicle development and stimulating granulosa cell proliferation. Mutations cause premature ovarian failure 14, which follows autosomal recessive inheritance. The gene is not highly constrained against loss-of-function variants (pLI near 0), consistent with the recessive inheritance pattern observed clinically.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Premature ovarian failure 14MIM #618014

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Premature ovarian failure 14; no ClinGen or GenCC tier

Active trials

138

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.19

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.19LOEUF

pLI 0.000

Z-score 1.05

OE 0.70 (0.43–1.19)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.57Z-score

OE missense 1.10 (1.00–1.22)

259 obs / 234.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.70 (0.43–1.19)

0≤0.351.4

Missense OE?1.10 (1.00–1.22)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 10 / 14.3Missense obs/exp: 259 / 234.6Syn Z: -0.57

Background carrier burden — how many people carry a rare variant somewhere in GDF9?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 85

606 rare PASS variants

Rare truncating (LoF)

1 in 860

92 rare PASS variants

Rare synonymous (reference)

1 in 180

217 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GDF9. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 140	1 in 920
South Asian	~43k	1 in 69	1 in 2,900
Remaining (unassigned)	~30k	1 in 75	1 in 770
European (Finnish)	~27k	1 in 340	1 in 4,500
Admixed American	~22k	1 in 78	1 in 1,600
African / African American	~21k	1 in 51	1 in 1,300
East Asian	~20k	1 in 100	1 in 1,000
Ashkenazi Jewish	~13k	1 in 210	1 in 1,200
Middle Eastern	~2,884	1 in 110	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓