TGFB3
protein-codingtransforming growth factor beta 3, the group of Transforming growth factor beta family
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 a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. This protein is involved in embryogenesis and cell differentiation, and may play a role in wound healing. Mutations in this gene are a cause of aortic aneurysms and dissections, as well as familial arrhythmogenic right ventricular dysplasia 1. [provided by RefSeq, Aug 2016]
- ARVD1
- ARVD
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~24.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014262
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0018954
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007152
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014262
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014262
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0014262
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0019625
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0016587
Submitter: ClinGen
TGFB: Arrythmogenic Right Ventricular Cardiomyopathy Mode of Inheritance: Autosomal dominant inheritance (HP:0000006) HGNC: 11769 MONDO:0016587 Expert Panel: Arrythmogenic Right Ventricular Cardiomyopathy Eleven papers were reviewed related to TGFB and ARVD (7951245, 15639475, 20864495, 222232248, 20124997, 15639468, 11127465, 12529708, 22878021, 24238504, Rampazzo A. Cardiovasc Res. 2012; 96: 191-194). It all started in 1994 with linkage to markers on chromosome 14q42.3 in a large Italian family (7951245) and followed by linkage to this region in several other Italian families and sequence analysis of candidate genes by the same group in 2000, 2003, 2005 and reviewed in 2012 (11127465, 12529708, 15639475, Rampazzo A. Cardiovasc Res. 2012; 96: 191-194). In six of 28 families linkage to 14q23-q24 was found; in two families, significantly positive lod scores were obtained with markers closely linked to ARVD1 locus (11127465). One family 112 had a LOD score of 5.2 (affected only LOD score of 2.71) another family 119 had a LOD score of 1.51. The critical interval for ARVD1 contained 40 known genes; 6 of them (POMT2, KIAA0759, KIAA1036, C14orf4, TAIL1 and TGFb3) were unsuccessfully screened for pathogenic ARVC mutations in the coding exons (12529708). In family 112 a non-coding variant (Chr14(GRCh37):g.76447266C>T; NM_003239.4(TGFB3):c.-30G>A, in the paper indicated as c.-36G>A) was identified in TGFB. This variant is observed 10 times in 249028 reference alleles from gnomAD. In an unrelated ARVD proband a TGFB variant was found in the 3’UTR (Chr14(GRCh37):g.76425035G>A: NM_003239.4(TGFB3):c.*495C>T, in the paper indicated as c.1723C>T) . This variant was not observed in 30272 reference alleles from gnomAD. Both variants were tested in a Luciferase C2C12 expression assay and both showed a 2.5 times increased activity compared to wildtype (15639475). In the review paper Rampazzo describes that in two unrelated families with linkage to this region showed no mutations in TGFB3 coding sequences, UTRs and promoter region and that in one of these two families, a large deletion encompassing the entire PKP2 gene was identified (15639475). Two coding variants of unknown significance were observed in this gene in two ARVD probands in another study (24238504). Total genetic evidence points calculated = 1.2; Total experimental evidence points calculated = 1; Total awarded points = 2.2; Final classification = Limited.
Inheritance Pattern: AD
Disease ID:MONDO:0016587
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014262
Submitter: G2P
Inheritance Pattern: Unknown
Disease ID:MONDO:0019625
Submitter: ClinGen
Inheritance Pattern: AD
Disease ID:MONDO:0014262
Submitter: Illumina
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Musculoskeletal
Intervention: Cardiovascular
Rationale: Individuals with Arrhythmogenic right ventricular dysplasia may manifest with syncope, cardiac arrest, and sudden death, and surveillance may allow early diagnosis of sequelae; Preventive measures (eg, with antiarrhythmic pharmacologic agents and/or ICD placement) may be beneficial, though some individuals may require heart transplantation; Individuals with Loeys-Dietz syndrome 5 (Reinhoff syndrome) have been described with cardiovascular anomalies including structural abnormalities and aortic aneurysms as well as arrhythmia, and awareness may allow early management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TGFB3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003239.5. 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 | 4 | 151 | 1 | 157 | |
| missense | 5 | 12 | 313 | 13 | 2 | 345 |
| nonsense | 11 | 9 | 2 | 22 | ||
| start loss | 2 | 2 | ||||
| frameshift | 24 | 10 | 5 | 39 | ||
| splice donor/acceptor (+/-2bp) | 5 | 17 | 3 | 25 | ||
| Total | 45 | 49 | 329 | 164 | 3 | 590 |
Highest pathogenic variant AF is 0.000009912448
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003230.1 | 7 | MANE Select | |
| Ensembl | ENSP00000238682.3 | 7 | MANE Select | |
| RefSeq | NP_001316867.1 | 5 | Standard | |
| RefSeq | NP_001316868.1 | 7 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| tgfb3 | Danio rerio | Structure: ventral wall of dorsal aorta Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Chronic myeloid leukemia - Homo sapiens (human)
- Gastric cancer - Homo sapiens (human)
- TGF-beta signaling pathway - Homo sapiens (human)
- Renal cell carcinoma - Homo sapiens (human)
- AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
Biological Process
- activation of MAPK activity
- response to hypoxia
- in utero embryonic development
- platelet degranulation
- transforming growth factor beta receptor signaling pathway
Molecular Function
- type II transforming growth factor beta receptor binding
- cytokine activity
- transforming growth factor beta receptor binding
- protein binding
- growth factor activity
Cellular Component
- extracellular region
- extracellular space
- nucleus
- plasma membrane
- cell surface
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000238682
- Coding exons
- 7
- Length
- 24893
- Individuals with no LoFs
- 125746
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125748
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.66 | 162 | 233 | 0.694 | 0.0000152 | 2713 |
| Missense (PolyPhen) | 51 | 95.197 | 0.53573 | 1109 | ||
| Synonymous | -1.33 | 110 | 93.6 | 1.18 | 0.00000565 | 810 |
| Loss of Function | 3.67 | 1 | 17.6 | 0.0568 | 9.55e-7 | 214 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transforming growth factor beta-3 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-3 (TGF-beta-3) chains, which constitute the regulatory and active subunit of TGF-beta-3, respectively. {ECO:0000250|UniProtKB:P01137, ECO:0000250|UniProtKB:P04202}.; FUNCTION: Transforming growth factor beta-3: Multifunctional protein that regulates embryogenesis and cell differentiation and is required in various processes such as secondary palate development (By similarity). Activation into mature form follows different steps: following cleavage of the proprotein in the Golgi apparatus, Latency-associated peptide (LAP) and Transforming growth factor beta-3 (TGF-beta-3) chains remain non-covalently linked rendering TGF-beta-3 inactive during storage in extracellular matrix (By similarity). At the same time, LAP chain interacts with 'milieu molecules', such as LTBP1 and LRRC32/GARP that control activation of TGF-beta-3 and maintain it in a latent state during storage in extracellular milieus (By similarity). TGF-beta-3 is released from LAP by integrins: integrin-binding results in distortion of the LAP chain and subsequent release of the active TGF-beta-3 (By similarity). Once activated following release of LAP, TGF-beta-3 acts by binding to TGF-beta receptors (TGFBR1 and TGFBR2), which transduce signal (By similarity). {ECO:0000250|UniProtKB:P01137, ECO:0000250|UniProtKB:P04202, ECO:0000250|UniProtKB:P17125}.;
- Disease
- DISEASE: Arrhythmogenic right ventricular dysplasia, familial, 1 (ARVD1) [MIM:107970]: A congenital heart disease characterized by infiltration of adipose and fibrous tissue into the right ventricle and loss of myocardial cells, resulting in ventricular and supraventricular arrhythmias. {ECO:0000269|PubMed:15639475}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Loeys-Dietz syndrome 5 (LDS5) [MIM:615582]: A form of Loeys-Dietz syndrome, a syndrome with widespread systemic involvement characterized by arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. LDS5 additional variable features include mitral valve disease, skeletal overgrowth, cervical spine instability, and clubfoot deformity. LDS5 patients do not manifest remarkable aortic or arterial tortuosity, and there is no strong evidence for early aortic dissection. {ECO:0000269|PubMed:23824657}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.784
Intolerance Scores
- LoFtool
- 0.118
- RVIS EVS
- -0.6
- RVIS percentile EVS
- 17.75
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.988
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |