TGFB1
protein-codingtransforming growth factor beta 1, 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 TGFB family members. This encoded protein regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors including interferon gamma and tumor necrosis factor alpha. This gene is frequently upregulated in tumor cells, and mutations in this gene result in Camurati-Engelmann disease. [provided by RefSeq, Aug 2016]
- TGFB
- DPD1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~52.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0032601
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007542
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0700385
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007542
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0032601
Submitter: ClinGen
*TGFB1 *was first reported in relation to autosomal recessive inflammatory bowel disease, immunodeficiency, and encephalopathy in 2018 (Koltraz et al., PMID:29483653). Evidence of inflammatory bowel disease, immunodeficiency, and encephalopathy (IBDIMDE) is predicted to be caused by a homozygous or compound heterozygous mutation in the *TGFB1 *gene. Three variants (missense) that have been reported in three patients in one publication (PMID:29483653) are included in this curation. Phenotypes varied but severe inflammatory bowel disesase and central nervous system disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy were common features. While TGFB1 gene polymorphisms have previously been described as potential risk for development of inflammatory bowel disease, this association is controversial and has not been consistently replicated. (PMID 24074435, PMID: 22140658). The gene-disease relationship is supported by two animal models. (PMIDs: 17481928, 1436033, 29204904). Shull et al. (PMID 1436033) observed that mice deficient in TGF-beta 1 developed a wasting syndrome characterized by a multifocal, mixed multi-organ inflammatory cell response affecting heart, stomach, liver, lung, pancreas, salivary gland and striated muscle. Li et al described mice with T cell-specific deletion of TGFB1 - mice developed severe colitis, with inflammatory infiltrates involving the lung and liver as well. In summary, there is limited evidence to support the role of *TGFB1* in autosomal recessive inflammatory bowel disease, immunodeficiency, and encephalopathy. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.This classification was approved by the ClinGen Primary Immune Regulatory Disorders GCEP on the meeting date November 19th, 2024 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0032601
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007542
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0032601
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007542
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0032601
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007542
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009061
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Hematologic; Musculoskeletal; Neurologic
Intervention: Allergy/Immunology/Infectious; Musculoskeletal
Rationale: In Camurati-Engelmann disease, medical management (eg, corticosteroids and/or losartan) may be beneficial to help with many manifestations, including pain, gait disturbances, anemia, hepatosplenomegaly, and exercise intolerance; In Inflammatory bowel disease, immunodeficiency, and encephalopathy, individuals have been reported with recurrent infections and immunologic manifestations affecting multiple organ systems, and awareness may allow management related to these sequelae
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TGFB1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000660.7. 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 | 7 | 113 | 2 | 122 | ||
| missense | 4 | 6 | 253 | 7 | 270 | |
| nonsense | 1 | 5 | 6 | |||
| start loss | 0 | |||||
| frameshift | 1 | 11 | 12 | |||
| splice donor/acceptor (+/-2bp) | 6 | 6 | ||||
| Total | 4 | 8 | 282 | 120 | 2 | 416 |
Highest pathogenic variant AF is 0.000013635496
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000651.3 | 7 | MANE Select | |
| Ensembl | ENSP00000221930.4 | 7 | MANE Select | |
| Ensembl | ENSP00000504008.1 | 6 | Standard | |
| Ensembl | ENSP00000504769.1 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| tgfb1a | Danio rerio | Structure: otolith Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Agents Acting on the Renin-Angiotensin System Pathway, Pharmacodynamics
- Chronic myeloid leukemia - Homo sapiens (human)
- Gastric cancer - Homo sapiens (human)
- Relaxin signaling pathway - Homo sapiens (human)
- TGF-beta signaling pathway - Homo sapiens (human)
Biological Process
- obsolete protein import into nucleus, translocation
- negative regulation of transcription by RNA polymerase II
- MAPK cascade
- vasculogenesis
- ureteric bud development
Molecular Function
- antigen binding
- type II transforming growth factor beta receptor binding
- cytokine activity
- transforming growth factor beta receptor binding
- protein binding
Cellular Component
- extracellular region
- extracellular space
- nucleus
- cytoplasm
- Golgi lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000221930
- Coding exons
- 7
- Length
- 52325
- Individuals with no LoFs
- 125742
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 6
- Defined
- 125748
- p
- 0.0000239
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.86 | 154 | 234 | 0.657 | 0.0000149 | 2457 |
| Missense (PolyPhen) | 35 | 85.116 | 0.4112 | 885 | ||
| Synonymous | 1.65 | 88 | 110 | 0.800 | 0.00000703 | 808 |
| Loss of Function | 2.80 | 6 | 19.3 | 0.311 | 0.00000120 | 198 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000027 | 0.000026 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transforming growth factor beta-1 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains, which constitute the regulatory and active subunit of TGF-beta-1, respectively. {ECO:0000269|PubMed:29109152, ECO:0000303|PubMed:27252363}.; FUNCTION: Transforming growth factor beta-1: Multifunctional protein that regulates the growth and differentiation of various cell types and is involved in various processes, such as normal development, immune function, microglia function and responses to neurodegeneration (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-1 (TGF-beta-1) chains remain non- covalently linked rendering TGF-beta-1 inactive during storage in extracellular matrix (PubMed:29109152). At the same time, LAP chain interacts with 'milieu molecules', such as LTBP1, LRRC32/GARP and LRRC33/NRROS that control activation of TGF-beta-1 and maintain it in a latent state during storage in extracellular milieus (PubMed:2022183, PubMed:8617200, PubMed:8939931, PubMed:19750484, PubMed:22278742, PubMed:19651619). TGF-beta-1 is released from LAP by integrins (ITGAV:ITGB6 or ITGAV:ITGB8): integrin-binding to LAP stabilizes an alternative conformation of the LAP bowtie tail and results in distortion of the LAP chain and subsequent release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447). Once activated following release of LAP, TGF- beta-1 acts by binding to TGF-beta receptors (TGFBR1 and TGFBR2), which transduce signal (PubMed:20207738). While expressed by many cells types, TGF-beta-1 only has a very localized range of action within cell environment thanks to fine regulation of its activation by Latency-associated peptide chain (LAP) and 'milieu molecules' (By similarity). Plays an important role in bone remodeling: acts as a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts (By similarity). Can promote either T- helper 17 cells (Th17) or regulatory T-cells (Treg) lineage differentiation in a concentration-dependent manner (By similarity). At high concentrations, leads to FOXP3-mediated suppression of RORC and down-regulation of IL-17 expression, favoring Treg cell development (By similarity). At low concentrations in concert with IL-6 and IL-21, leads to expression of the IL-17 and IL-23 receptors, favoring differentiation to Th17 cells (By similarity). Stimulates sustained production of collagen through the activation of CREB3L1 by regulated intramembrane proteolysis (RIP) (PubMed:25310401). Mediates SMAD2/3 activation by inducing its phosphorylation and subsequent translocation to the nucleus (PubMed:25893292). Can induce epithelial-to- mesenchymal transition (EMT) and cell migration in various cell types (PubMed:25893292). {ECO:0000250|UniProtKB:P04202, ECO:0000269|PubMed:19651619, ECO:0000269|PubMed:19750484, ECO:0000269|PubMed:20207738, ECO:0000269|PubMed:2022183, ECO:0000269|PubMed:22278742, ECO:0000269|PubMed:25310401, ECO:0000269|PubMed:25893292, ECO:0000269|PubMed:28117447, ECO:0000269|PubMed:29109152, ECO:0000269|PubMed:8617200, ECO:0000269|PubMed:8939931}.;
- Disease
- DISEASE: Camurati-Engelmann disease (CAEND) [MIM:131300]: An autosomal dominant disorder characterized by hyperostosis and sclerosis of the diaphyses of long bones. The disease typically presents in early childhood with pain, muscular weakness and waddling gait, and in some cases other features such as exophthalmos, facial paralysis, hearing difficulties and loss of vision. {ECO:0000269|PubMed:10973241, ECO:0000269|PubMed:11062463, ECO:0000269|PubMed:12493741, ECO:0000269|PubMed:12843182, ECO:0000269|PubMed:15103729}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.998
Intolerance Scores
- LoFtool
- 0.219
- RVIS EVS
- -0.12
- RVIS percentile EVS
- 44.89
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.997
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |