GDF3
protein-codinggrowth differentiation factor 3, 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 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]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013376
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0013375
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013375
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0000170
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0016520
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013377
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Ophthalmologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: Microphthalmia, isolated 4; Microphthalmia with coloboma 6, digenic; Multiple synostoses syndrome 4; Klippel-Feil syndrome 1, autosomal dominant; Leber congenital amaurosis 17
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GDF3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_020634.3. 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 | 1 | 12 | 2 | 15 | ||
| missense | 2 | 59 | 6 | 67 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 2 | 63 | 18 | 2 | 85 |
Highest pathogenic variant AF is 0.000007524846
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_065685.1 | 2 | MANE Select | |
| Ensembl | ENSP00000331745.3 | 2 | MANE Select | |
| Ensembl | ENSP00000807326.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gdf3 | Danio rerio | Structure: hindbrain neural keel Quality: increased width abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Endoderm Differentiation
- Mesodermal Commitment Pathway
- GPCR signaling-G alpha q
- GPCR signaling-cholera toxin
- GPCR signaling-pertussis toxin
Biological Process
- skeletal system development
- eye development
- in utero embryonic development
- response to dietary excess
- endoderm development
Molecular Function
- cytokine activity
- transforming growth factor beta receptor binding
- growth factor activity
- protein kinase binding
Cellular Component
- extracellular space
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000329913
- Coding exons
- 2
- Length
- 5995
- Individuals with no LoFs
- 125710
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 37
- Defined
- 125747
- p
- 0.000147
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.116 | 202 | 197 | 1.02 | 0.0000105 | 2378 |
| Missense (PolyPhen) | 54 | 69.164 | 0.78076 | 872 | ||
| Synonymous | 0.105 | 81 | 82.2 | 0.985 | 0.00000412 | 746 |
| Loss of Function | 0.838 | 8 | 11.0 | 0.727 | 5.21e-7 | 134 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.0010 | 0.00099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00016 | 0.00016 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Growth factor involved in early embryonic development and adipose-tissue homeostasis. During embryogenesis controls formation of anterior visceral endoderm and mesoderm and the establishment of anterior-posterior identity through a receptor complex comprising the receptor ACVR1B and the coreceptor TDGF1/Cripto (By similarity). Regulates adipose-tissue homeostasis and energy balance under nutrient overload in part by signaling through the receptor complex based on ACVR1C and TDGF1/Cripto (PubMed:21805089). {ECO:0000250|UniProtKB:Q07104, ECO:0000269|PubMed:21805089}.;
- Disease
- DISEASE: Klippel-Feil syndrome 3, autosomal dominant (KFS3) [MIM:613702]: A skeletal disorder characterized by congenital fusion of cervical vertebrae. It is due to a failure in the normal segmentation of vertebrae during the early weeks of fetal development. The clinical triad consists of short neck, low posterior hairline, and limited neck movement. {ECO:0000269|PubMed:19864492}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Microphthalmia, isolated, with coloboma, 6 (MCOPCB6) [MIM:613703]: A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). {ECO:0000269|PubMed:19864492}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Microphthalmia, isolated, 7 (MCOP7) [MIM:613704]: A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. {ECO:0000269|PubMed:19864492}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.114
Intolerance Scores
- LoFtool
- 0.376
- RVIS EVS
- 0.42
- RVIS percentile EVS
- 76.96
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.00129
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |