GDF3

Chr 12AD

growth differentiation factor 3

Also known as: KFS3, MCOP7, MCOPCB6

NCBI Gene: 9573 ENSG00000184344 UniProt: Q9NR23 OMIM: 606522

This gene encodes a secreted growth factor of the TGF-beta superfamily that regulates early embryonic development, particularly ocular and skeletal formation. Autosomal dominant mutations cause Klippel-Feil syndrome, isolated microphthalmia, and microphthalmia with coloboma, affecting craniofacial and skeletal development. The gene shows low constraint to loss-of-function variation, consistent with its dominant inheritance pattern.

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 plays a role ocular and skeletal development. Mutations in this gene are associated with microphthalmia, coloboma, and skeletal abnormalities in human patients. [provided by RefSeq, Aug 2016]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Klippel-Feil syndrome 3, autosomal dominantMIM #613702

Microphthalmia, isolated 7MIM #613704

Microphthalmia, isolated, with coloboma 6MIM #613703

UniProtMicrophthalmia/Coloboma 6

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Klippel-Feil syndrome 3, autosomal dominant; Microphthalmia, isolated 7 (+1); no ClinGen or GenCC tier

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.31

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.31LOEUF

pLI 0.000

Z-score 0.84

OE 0.73 (0.43–1.31)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.12Z-score

OE missense 1.02 (0.91–1.15)

202 obs / 197.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.73 (0.43–1.31)

0≤0.351.4

Missense OE?1.02 (0.91–1.15)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 8 / 11.0Missense obs/exp: 202 / 197.4Syn Z: 0.10

Background carrier burden — how many people carry a rare variant somewhere in GDF3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 150

486 rare PASS variants

Rare truncating (LoF)

1 in 2,000

58 rare PASS variants

Rare synonymous (reference)

1 in 340

175 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GDF3. 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 280	1 in 1,900
South Asian	~43k	1 in 87	1 in 3,900
Remaining (unassigned)	~30k	1 in 120	1 in 4,300
European (Finnish)	~27k	1 in 530	≈ 1 in 27,000
Admixed American	~22k	1 in 160	≈ 1 in 7,500
African / African American	~21k	1 in 110	1 in 3,600
East Asian	~20k	1 in 180	1 in 1,100
Ashkenazi Jewish	~13k	1 in 650	1 in 570
Middle Eastern	~2,884	1 in 100	≈ 1 in 1,400

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 ↓