GDF3

growth differentiation factor 3, the group of Transforming growth factor beta superfamily

Basic information

Region (hg38): 12:7689783-7695775

Links

ENSG00000184344 ∙ NCBI:9573 ∙ OMIM:606522 ∙ HGNC:4218 ∙ Uniprot:Q9NR23 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• isolated microphthalmia 7 (Limited), mode of inheritance: AD
• Klippel-Feil syndrome 3, autosomal dominant (Limited), mode of inheritance: AD
• microphthalmia, isolated, with coloboma 6 (Limited), mode of inheritance: AD
• isolated Klippel-Feil syndrome (Supportive), mode of inheritance: AD
• isolated anophthalmia-microphthalmia syndrome (Supportive), mode of inheritance: AD
• microphthalmia, isolated, with coloboma (Supportive), mode of inheritance: AD
• Klippel-Feil syndrome 3, autosomal dominant (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Microphthalmia, isolated 7; Microphthalmia with coloboma 6; Klippel-Feil syndrome 3, autosomal dominant	AD/Digenic	General	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	Musculoskeletal; Ophthalmologic	15241163; 19864492
Microphthalmia, isolated 4; Microphthalmia with coloboma 6, digenic; Multiple synostoses syndrome 4; Klippel-Feil syndrome 1, autosomal dominant; Leber congenital amaurosis 17

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GDF3 gene.

• not provided (20 variants)
• Klippel-Feil syndrome 3, autosomal dominant (15 variants)
• Inborn genetic diseases (12 variants)
• not specified (2 variants)
• Microphthalmia, isolated, with coloboma 6 (2 variants)
• Isolated microphthalmia 7 (1 variants)
• Supernumerary ribs;Scoliosis;Hemivertebrae;Missing ribs (1 variants)
• Klippel-Feil syndrome 3, autosomal dominant;Isolated microphthalmia 7;Microphthalmia, isolated, with coloboma 6 (1 variants)
• GDF3-related condition (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GDF3 gene is commonly pathogenic or not.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				5	4	9
missense		2	20	3	3	28
nonsense						0
start loss						0
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region						0
non coding					5	5
Total	0	2	22	8	12

Variants in GDF3

This is a list of pathogenic ClinVar variants found in the GDF3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-7689882-C-G			Uncertain significance (Sep 19, 2022)
12-7689916-A-G		not specified	Uncertain significance (Dec 14, 2021)
12-7689937-CA-C			Uncertain significance (Apr 07, 2023)
12-7689991-C-G		Klippel-Feil syndrome 3, autosomal dominant	Benign (Jan 30, 2024)
12-7689999-G-A		Microphthalmia, isolated, with coloboma 6	Uncertain significance (Mar 30, 2012)
12-7690000-G-T			Uncertain significance (Dec 30, 2022)
12-7690029-G-A		not specified	Uncertain significance (Jan 04, 2024)
12-7690059-A-C			Likely pathogenic (Feb 23, 2017)
12-7690059-A-G		Isolated microphthalmia 7 • Klippel-Feil syndrome 3, autosomal dominant • not specified	Benign (Mar 13, 2023)
12-7690063-A-G		Klippel-Feil syndrome 3, autosomal dominant	Uncertain significance (Mar 26, 2019)
12-7690077-A-T		not specified	Uncertain significance (Mar 01, 2023)
12-7690153-G-A		Microphthalmia, isolated, with coloboma 6 • not specified	Uncertain significance (May 04, 2022)
12-7690177-G-A		Microphthalmia, isolated, with coloboma 6 • Klippel-Feil syndrome 3, autosomal dominant • Scoliosis;Missing ribs;Supernumerary ribs;Hemivertebrae • GDF3-related disorder	Conflicting classifications of pathogenicity (Jan 18, 2024)
12-7690204-T-C		not specified	Uncertain significance (Apr 05, 2023)
12-7690222-C-T		Klippel-Feil syndrome 3, autosomal dominant	Uncertain significance (Mar 05, 2020)
12-7690259-G-A			Likely benign (Jun 01, 2022)
12-7690264-T-C		Klippel-Feil syndrome 3, autosomal dominant	Uncertain significance (Oct 18, 2017)
12-7690277-G-T		GDF3-related disorder	Likely benign (Aug 09, 2021)
12-7690336-C-T		Klippel-Feil syndrome 3, autosomal dominant	Benign (Jan 30, 2024)
12-7690338-G-A		Klippel-Feil syndrome 3, autosomal dominant	Likely benign (Dec 31, 2019)
12-7690389-C-T		Isolated microphthalmia 7	Pathogenic (Jan 15, 2010)
12-7690390-G-A		Klippel-Feil syndrome 3, autosomal dominant • Klippel-Feil syndrome 3, autosomal dominant;Isolated microphthalmia 7;Microphthalmia, isolated, with coloboma 6 • GDF3-related disorder	Benign/Likely benign (Sep 09, 2022)
12-7690394-G-A		Klippel-Feil syndrome 3, autosomal dominant • GDF3-related disorder	Benign (Dec 22, 2022)
12-7690413-G-A		not specified	Uncertain significance (Mar 01, 2023)
12-7690464-C-T		not specified	Likely benign (Nov 10, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GDF3	protein_coding	protein_coding	ENST00000329913	2	5995

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000407	0.638	125710	0	37	125747	0.000147

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.116	202	197	1.02	0.0000105	2378
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000181	0.000181
Ashkenazi Jewish	0.000999	0.000993
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.000159	0.000158
Middle Eastern	0.00	0.00
South Asian	0.0000653	0.0000653
Other	0.000489	0.000489

dbNSFP

Source: dbNSFP

• 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.
• Pathway: Endoderm Differentiation;Mesodermal Commitment Pathway;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)

Recessive Scores

• pRec: 0.114

Intolerance Scores

• loftool: 0.376
• rvis_EVS: 0.42
• rvis_percentile_EVS: 76.96

Haploinsufficiency Scores

• pHI: 0.325
• hipred: N
• hipred_score: 0.173

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.00129

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gdf3
• Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; embryo phenotype; growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: gdf3
• Affected structure: hindbrain neural keel
• Phenotype tag: abnormal
• Phenotype quality: increased width

Gene ontology

• Biological process: skeletal system development;eye development;in utero embryonic development;response to dietary excess;endoderm development;mesoderm development;regulation of cell fate commitment;regulation of signaling receptor activity;positive regulation of pathway-restricted SMAD protein phosphorylation;BMP signaling pathway;negative regulation of BMP signaling pathway;notochord development;somite rostral/caudal axis specification;regulation of apoptotic process;regulation of MAPK cascade;positive regulation of fat cell differentiation;negative regulation of epidermal cell differentiation;negative regulation of myoblast differentiation;cell development;formation of anatomical boundary;SMAD protein signal transduction;primitive streak formation
• Cellular component: extracellular space;cytoplasm
• Molecular function: cytokine activity;transforming growth factor beta receptor binding;growth factor activity;protein kinase binding