GDF5

growth differentiation factor 5, the group of Transforming growth factor beta superfamily|MicroRNA protein coding host genes

Basic information

Region (hg38): 20:35433346-35454746

Links

ENSG00000125965 ∙ NCBI:8200 ∙ OMIM:601146 ∙ HGNC:4220 ∙ Uniprot:P43026 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• acromesomelic dysplasia 2A (Definitive), mode of inheritance: AR
• acromesomelic dysplasia 2B (Definitive), mode of inheritance: AR
• proximal symphalangism 1A (Definitive), mode of inheritance: AD
• acromesomelic dysplasia 2C, Hunter-Thompson type (Definitive), mode of inheritance: AR
• brachydactyly type C (Definitive), mode of inheritance: Semidominant
• acromesomelic dysplasia 2A (Moderate), mode of inheritance: AR
• acromesomelic dysplasia 2C, Hunter-Thompson type (Supportive), mode of inheritance: AR
• acromesomelic dysplasia 2A (Supportive), mode of inheritance: AR
• acromesomelic dysplasia 2B (Supportive), mode of inheritance: AR
• multiple synostoses syndrome (Supportive), mode of inheritance: AD
• proximal symphalangism (Supportive), mode of inheritance: AD
• Angel-shaped phalango-epiphyseal dysplasia (Supportive), mode of inheritance: AD
• brachydactyly type C (Supportive), mode of inheritance: AD
• brachydactyly type A1 (Supportive), mode of inheritance: AD
• brachydactyly type A2 (Supportive), mode of inheritance: AD
• acromesomelic dysplasia 2A (Strong), mode of inheritance: AR
• brachydactyly type A1C (Strong), mode of inheritance: AD
• symphalangism, proximal, 1B (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Acromesomelic dysplasia 2C; Acromesomelic dysplasia 2B; Multiple synostoses syndrome 2; Acromesomelic dysplasia 2A; Symphalangism, proximal 1B; Brachydactyly, type A1, C; Brachydactyly, type A2; Brachydactyly, type C; Acromesomelic dysplasia 2C	AD/AR	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	13953230; 14159881; 4850715; 964999; 2624264; 2703235; 2363425; 8954778; 8589725; 9288098; 9489798; 12357473; 12121354; 12567410; 14735582; 16127465; 16222676; 16532400; 16014698; 16957682; 16892395; 17384641; 18629880; 18283415; 19956691; 20683927

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GDF5 gene.

• not provided (206 variants)
• Grebe syndrome (43 variants)
• Acromesomelic dysplasia 2B (41 variants)
• Multiple synostoses syndrome 2 (40 variants)
• Acromesomelic dysplasia 2C, Hunter-Thompson type (40 variants)
• Brachydactyly (40 variants)
• Inborn genetic diseases (21 variants)
• not specified (11 variants)
• Brachydactyly type A2 (3 variants)
• - (3 variants)
• Brachydactyly type C (3 variants)
• Symphalangism-brachydactyly syndrome (1 variants)
• Brachydactyly type A1C (1 variants)
• GDF5-related condition (1 variants)
• Osteoarthritis, hip (1 variants)
• Chondrodysplasia (1 variants)
• 9 conditions (1 variants)
• Acromesomelic dysplasia (1 variants)
• Symphalangism, proximal, 1B (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GDF5 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			3	71	1	75
missense	2	4	88	6	3	103
nonsense	3	5	2			10
start loss			1			1
frameshift	12					12
inframe indel			3			3
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			5	12	15	32
Total	17	9	102	89	19

Highest pathogenic variant AF is 0.0000131

Variants in GDF5

This is a list of pathogenic ClinVar variants found in the GDF5 region.

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

Position	Type	Phenotype	Significance	ClinVar
20-35433389-A-G		Grebe syndrome • Acromesomelic dysplasia 2B • Brachydactyly • Multiple synostoses syndrome 2 • Acromesomelic dysplasia 2C, Hunter-Thompson type	Benign/Likely benign (Jan 13, 2018)
20-35433441-C-T		Acromesomelic dysplasia 2B • Grebe syndrome • Multiple synostoses syndrome 2 • Acromesomelic dysplasia 2C, Hunter-Thompson type • Brachydactyly	Benign/Likely benign (May 12, 2021)
20-35433484-A-G		Grebe syndrome • Acromesomelic dysplasia 2B • Brachydactyly • Multiple synostoses syndrome 2 • Acromesomelic dysplasia 2C, Hunter-Thompson type	Benign (May 12, 2021)
20-35433520-G-A		Acromesomelic dysplasia 2B • Multiple synostoses syndrome 2 • Acromesomelic dysplasia 2C, Hunter-Thompson type • Grebe syndrome • Brachydactyly	Benign/Likely benign (Jan 12, 2018)
20-35433522-A-G		Brachydactyly • Multiple synostoses syndrome 2 • Acromesomelic dysplasia 2B • Acromesomelic dysplasia 2C, Hunter-Thompson type • Grebe syndrome	Benign/Likely benign (Jan 13, 2018)
20-35433574-T-G		Acromesomelic dysplasia 2C, Hunter-Thompson type • Multiple synostoses syndrome 2 • Brachydactyly • Acromesomelic dysplasia 2B • Grebe syndrome	Benign (May 12, 2021)
20-35433650-C-G		Acromesomelic dysplasia 2B • Multiple synostoses syndrome 2 • Grebe syndrome • Brachydactyly • Acromesomelic dysplasia 2C, Hunter-Thompson type	Conflicting classifications of pathogenicity (Jan 12, 2018)
20-35433716-C-A		Acromesomelic dysplasia 2C, Hunter-Thompson type • Brachydactyly • Multiple synostoses syndrome 2 • Grebe syndrome • Acromesomelic dysplasia 2B	Benign (Sep 01, 2020)
20-35433743-C-T		Multiple synostoses syndrome 2 • Acromesomelic dysplasia 2B • Brachydactyly • Grebe syndrome • Acromesomelic dysplasia 2C, Hunter-Thompson type	Uncertain significance (Jan 13, 2018)
20-35433912-C-T			Likely benign (Dec 26, 2023)
20-35433915-G-A			Likely benign (Feb 04, 2023)
20-35433923-A-G			Uncertain significance (Sep 07, 2022)
20-35433924-C-A			Likely benign (Mar 23, 2022)
20-35433924-C-T			Likely benign (Jan 29, 2024)
20-35433927-C-T			Likely benign (Dec 09, 2023)
20-35433930-C-T			Likely benign (Jul 31, 2023)
20-35433932-C-A			Uncertain significance (Oct 07, 2023)
20-35433933-G-A			Likely benign (Dec 10, 2022)
20-35433939-G-A			Likely benign (Dec 04, 2023)
20-35433942-C-T			Likely benign (Jan 31, 2024)
20-35433944-C-T		Symphalangism, proximal, 1B	Pathogenic (Sep 01, 2006)
20-35433947-A-G			Uncertain significance (Aug 18, 2016)
20-35433947-ACTG-A			Uncertain significance (Jul 20, 2022)
20-35433948-C-T			Likely benign (Dec 20, 2023)
20-35433951-C-T			Likely benign (Mar 26, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GDF5	protein_coding	protein_coding	ENST00000374372	2	21424

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.670	0.330	125734	0	7	125741	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.894	273	318	0.859	0.0000214	3199
Missense in Polyphen		74	117.01	0.63245		1223
Synonymous	-1.21	166	147	1.13	0.0000103	1099
Loss of Function	3.10	3	16.7	0.180	0.00000116	158

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000161	0.000152
Ashkenazi Jewish	0.000102	0.0000992
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000190	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Growth factor involved in bone and cartilage formation. During cartilage development regulates differentiation of chondrogenic tissue through two pathways. Firstly, positively regulates differentiation of chondrogenic tissue through its binding of high affinity with BMPR1B and of less affinity with BMPR1A, leading to induction of SMAD1-SMAD5-SMAD8 complex phosphorylation and then SMAD protein signaling transduction (PubMed:24098149, PubMed:21976273, PubMed:15530414, PubMed:25092592). Secondly, negatively regulates chondrogenic differentiation through its interaction with NOG (PubMed:21976273). Required to prevent excessive muscle loss upon denervation. This function requires SMAD4 and is mediated by phosphorylated SMAD1/5/8 (By similarity). Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:11276205). {ECO:0000250|UniProtKB:P43027, ECO:0000269|PubMed:11276205, ECO:0000269|PubMed:15530414, ECO:0000269|PubMed:19229295, ECO:0000269|PubMed:19956691, ECO:0000269|PubMed:21976273, ECO:0000269|PubMed:24098149, ECO:0000269|PubMed:25092592}.
• Disease: DISEASE: Acromesomelic chondrodysplasia, Hunter-Thompson type (AMDH) [MIM:201250]: An autosomal recessive form of dwarfism. Patients have limb abnormalities, with the middle and distal segments being most affected and the lower limbs more affected than the upper. AMDH is characterized by normal axial skeletons and missing or fused skeletal elements within the hands and feet. {ECO:0000269|PubMed:8589725}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Brachydactyly C (BDC) [MIM:113100]: A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. Brachydactyly type C is characterized by deformity of the middle and proximal phalanges of the second and third fingers, sometimes with hypersegmentation of the proximal phalanx. The ring finger may be essentially normal and project beyond the others. {ECO:0000269|PubMed:14735582, ECO:0000269|PubMed:22828468, ECO:0000269|PubMed:25092592, ECO:0000269|PubMed:25820810}. Note=The disease is caused by mutations affecting the gene represented in this entry. Some BDC patients with GDF5 mutations also manifest clinical features of ASPED angel-shaped phalango- epiphyseal dysplasia (ASPED), an autosomal dominant skeletal abnormality characterized by a typical angel-shaped phalanx, brachydactyly, specific radiological findings, abnormal dentition, hip dysplasia, and delayed bone age. This suggests that BDC and ASPED are part of the same clinical spectrum (PubMed:22828468). {ECO:0000269|PubMed:22828468}.; DISEASE: Du Pan syndrome (DPS) [MIM:228900]: Rare autosomal recessive condition characterized by absence of the fibulae and severe acromesomelic limb shortening with small, non-functional toes. Although milder, the phenotype resembles the autosomal recessive Hunter-Thompson and Grebe types of acromesomelic chondrodysplasia. {ECO:0000269|PubMed:12121354, ECO:0000269|PubMed:16222676, ECO:0000269|PubMed:18629880}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Symphalangism, proximal 1B (SYM1B) [MIM:615298]: A disease characterized by the hereditary absence of the proximal interphalangeal joints. Distal interphalangeal joints are less frequently involved and metacarpophalangeal joints are rarely affected whereas carpal bone malformation and fusion are common. In the lower extremities, tarsal bone coalition is common. Conductive hearing loss is seen and is due to fusion of the stapes to the petrous part of the temporal bone. {ECO:0000269|PubMed:16127465, ECO:0000269|PubMed:16892395, ECO:0000269|PubMed:18283415}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Multiple synostoses syndrome 2 (SYNS2) [MIM:610017]: A bone disease characterized by multiple progressive joint fusions that commonly involve proximal interphalangeal, tarsal-carpal, humeroradial and cervical spine joints. Additional features can include progressive conductive deafness and facial dysmorphism. {ECO:0000269|PubMed:16532400, ECO:0000269|PubMed:19956691, ECO:0000269|PubMed:21976273, ECO:0000269|PubMed:24098149, ECO:0000269|Ref.18}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Brachydactyly A2 (BDA2) [MIM:112600]: A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. In brachydactyly type A2 shortening of the middle phalanges is confined to the index finger and the second toe, all other digits being more or less normal. Because of a rhomboid or triangular shape of the affected middle phalanx, the end of the second finger usually deviates radially. {ECO:0000269|PubMed:16127465, ECO:0000269|PubMed:18203755, ECO:0000269|PubMed:21976273}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Osteoarthritis 5 (OS5) [MIM:612400]: A degenerative disease of the joints characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone with sclerosis. Clinical symptoms include pain and joint stiffness often leading to significant disability and joint replacement. {ECO:0000269|PubMed:17384641}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Brachydactyly A1, C (BDA1C) [MIM:615072]: A form of brachydactyly type A1. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. Brachydactyly type A1 is characterized by middle phalanges of all the digits rudimentary or fused with the terminal phalanges. The proximal phalanges of the thumbs and big toes are short. BDA1C inheritance can be autosomal dominant or autosomal recessive. Autosomal dominant BDA1C has a milder phenotype. {ECO:0000269|PubMed:20683927, ECO:0000269|PubMed:24098149}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: TGF-beta signaling pathway - Homo sapiens (human);Hippo signaling pathway - Homo sapiens (human);Cytokine-cytokine receptor interaction - Homo sapiens (human);TGF-Core;Differentiation Pathway;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Extracellular matrix organization;Molecules associated with elastic fibres;Elastic fibre formation;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: 0.328

Intolerance Scores

• loftool: 0.158
• rvis_EVS: -0.07
• rvis_percentile_EVS: 48.69

Haploinsufficiency Scores

• pHI: 0.491
• hipred: Y
• hipred_score: 0.825
• ghis: 0.405

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.965

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gdf5
• Phenotype: limbs/digits/tail phenotype; skeleton 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); reproductive system phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: chondrocyte differentiation;transforming growth factor beta receptor signaling pathway;cell-cell signaling;response to mechanical stimulus;regulation of signaling receptor activity;positive regulation of pathway-restricted SMAD protein phosphorylation;embryonic limb morphogenesis;BMP signaling pathway;positive regulation of BMP signaling pathway;negative regulation of chondrocyte differentiation;positive regulation of chondrocyte differentiation;forelimb morphogenesis;hindlimb morphogenesis;regulation of multicellular organism growth;regulation of apoptotic process;regulation of MAPK cascade;negative regulation of neuron apoptotic process;ossification involved in bone remodeling;positive regulation of neuron differentiation;cell development;negative regulation of epithelial cell proliferation;regulation of SMAD protein signal transduction;SMAD protein signal transduction;chondroblast differentiation;negative regulation of mesenchymal cell apoptotic process
• Cellular component: extracellular region;extracellular space;plasma membrane
• Molecular function: cytokine activity;transforming growth factor beta receptor binding;protein binding;growth factor activity;BMP binding;identical protein binding