SMAD3
SMAD family member 3, the group of SMAD family
Basic information
Region (hg38): 15:67063762-67195173
Previous symbols: [ "MADH3" ]
Links
Phenotypes
GenCC
Source:
- aneurysm-osteoarthritis syndrome (Strong), mode of inheritance: AD
- aneurysm-osteoarthritis syndrome (Strong), mode of inheritance: AD
- aneurysm-osteoarthritis syndrome (Definitive), mode of inheritance: AD
- familial thoracic aortic aneurysm and aortic dissection (Supportive), mode of inheritance: AD
- aneurysm-osteoarthritis syndrome (Supportive), mode of inheritance: AD
- aneurysm-osteoarthritis syndrome (Strong), mode of inheritance: AD
- aneurysm-osteoarthritis syndrome (Definitive), mode of inheritance: AD
- familial thoracic aortic aneurysm and aortic dissection (Definitive), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Loeys-Dietz syndrome, type 3 | AD | Cardiovascular | Preventive measures and medical management may be helpful to help decrease morbidity, especially related to cardiovascular complications, which can result in sequelae such as sudden death, primarily due to aortic dissection and/or rupture | Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal | 21217753; 21778426; 22167769 |
ClinVar
This is a list of variants' phenotypes submitted to
- Familial thoracic aortic aneurysm and aortic dissection (716 variants)
- not provided (237 variants)
- Aneurysm-osteoarthritis syndrome (127 variants)
- Loeys-Dietz syndrome (110 variants)
- not specified (55 variants)
- Ehlers-Danlos syndrome (19 variants)
- Connective tissue disorder (6 variants)
- Cardiovascular phenotype (6 variants)
- Inborn genetic diseases (5 variants)
- SMAD3-related condition (4 variants)
- Familial aortopathy (2 variants)
- Thoracic aortic aneurysm (2 variants)
- See cases (2 variants)
- Isolated thoracic aortic aneurysm (2 variants)
- Arterial dissection;Cutaneous polyarteritis nodosa (1 variants)
- Aortic aneurysm, familial thoracic 6 (1 variants)
- Lung cancer (1 variants)
- Ascending aortic dissection (1 variants)
- SMAD3-Related Disorder (1 variants)
- Aortic aneurysm (1 variants)
- Coronary artery disorder (1 variants)
- Congenital aneurysm of ascending aorta (1 variants)
- Vascular dilatation (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the SMAD3 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 | 149 | 154 | ||||
| missense | 19 | 255 | 281 | |||
| nonsense | 21 | 29 | ||||
| start loss | 6 | |||||
| frameshift | 39 | 19 | 59 | |||
| inframe indel | 14 | 16 | ||||
| splice donor/acceptor (+/-2bp) | 12 | 16 | ||||
| splice region ? | 1 | 1 | 16 | 25 | 43 | |
| non coding ? | 99 | 96 | 44 | 240 | ||
| Total | 69 | 63 | 377 | 247 | 45 |
Highest pathogenic variant AF is 0.00000657
Variants in SMAD3
This is a list of pathogenic ClinVar variants found in the SMAD3 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 15-67065875-C-A | Loeys-Dietz syndrome • Familial thoracic aortic aneurysm and aortic dissection | Uncertain significance (Jun 14, 2016) | ||
| 15-67065890-T-G | Familial thoracic aortic aneurysm and aortic dissection • Aneurysm-osteoarthritis syndrome | Uncertain significance (Oct 15, 2021) | ||
| 15-67065911-G-A | Familial thoracic aortic aneurysm and aortic dissection • Aneurysm-osteoarthritis syndrome | Uncertain significance (Jan 12, 2018) | ||
| 15-67065915-G-T | Aneurysm-osteoarthritis syndrome • Familial thoracic aortic aneurysm and aortic dissection | Uncertain significance (Jan 13, 2018) | ||
| 15-67065938-C-T | Aneurysm-osteoarthritis syndrome • Loeys-Dietz syndrome | Uncertain significance (Jan 13, 2018) | ||
| 15-67065987-C-A | Familial thoracic aortic aneurysm and aortic dissection • Loeys-Dietz syndrome | Uncertain significance (Jun 14, 2016) | ||
| 15-67065991-A-C | Aneurysm-osteoarthritis syndrome • Familial thoracic aortic aneurysm and aortic dissection | Uncertain significance (Oct 11, 2021) | ||
| 15-67066016-C-G | Aneurysm-osteoarthritis syndrome | Uncertain significance (Jan 12, 2018) | ||
| 15-67066040-C-T | Familial thoracic aortic aneurysm and aortic dissection • Loeys-Dietz syndrome | Likely benign (Jun 14, 2016) | ||
| 15-67066055-C-T | Familial thoracic aortic aneurysm and aortic dissection • Aneurysm-osteoarthritis syndrome | Uncertain significance (Jan 13, 2018) | ||
| 15-67066117-C-T | Aneurysm-osteoarthritis syndrome | Uncertain significance (Jan 12, 2018) | ||
| 15-67066127-C-T | not specified • Loeys-Dietz syndrome • Aneurysm-osteoarthritis syndrome | Benign (Jan 13, 2018) | ||
| 15-67066132-C-T | not specified • Loeys-Dietz syndrome • Aneurysm-osteoarthritis syndrome | Benign (Jan 12, 2018) | ||
| 15-67066137-C-T | not specified | Likely benign (Oct 26, 2017) | ||
| 15-67066138-GCG-ACA | Familial thoracic aortic aneurysm and aortic dissection | Uncertain significance (Aug 05, 2020) | ||
| 15-67066140-G-A | not specified • Familial thoracic aortic aneurysm and aortic dissection • Aneurysm-osteoarthritis syndrome | Benign (Aug 16, 2019) | ||
| 15-67066145-C-T | Familial thoracic aortic aneurysm and aortic dissection • Ehlers-Danlos syndrome | Uncertain significance (Nov 08, 2022) | ||
| 15-67066146-TC-T | Aneurysm-osteoarthritis syndrome | Uncertain significance (Aug 15, 2023) | ||
| 15-67066150-C-A | Aneurysm-osteoarthritis syndrome | Uncertain significance (May 04, 2023) | ||
| 15-67066150-C-T | Aneurysm-osteoarthritis syndrome | Uncertain significance (Dec 18, 2023) | ||
| 15-67066153-C-G | Familial thoracic aortic aneurysm and aortic dissection | Uncertain significance (Dec 17, 2019) | ||
| 15-67066154-C-T | Familial thoracic aortic aneurysm and aortic dissection | Uncertain significance (Nov 08, 2022) | ||
| 15-67066155-A-C | Familial thoracic aortic aneurysm and aortic dissection | Pathogenic/Likely pathogenic (Dec 03, 2023) | ||
| 15-67066155-A-G | Aortic aneurysm | Pathogenic (-) | ||
| 15-67066155-A-T | Aneurysm-osteoarthritis syndrome • Familial thoracic aortic aneurysm and aortic dissection | Pathogenic/Likely pathogenic (Feb 24, 2021) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| SMAD3 | protein_coding | protein_coding | ENST00000327367 | 9 | 131433 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.798 | 0.202 | 125740 | 0 | 8 | 125748 | 0.0000318 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 3.48 | 97 | 253 | 0.384 | 0.0000164 | 2791 |
| Missense in Polyphen | 13 | 86.992 | 0.14944 | 1006 | ||
| Synonymous | -0.958 | 119 | 106 | 1.12 | 0.00000770 | 812 |
| Loss of Function | 3.66 | 4 | 22.9 | 0.175 | 0.00000118 | 238 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.00 | 0.00 |
| Ashkenazi Jewish | 0.0000992 | 0.0000992 |
| East Asian | 0.0000544 | 0.0000544 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.0000548 | 0.0000527 |
| Middle Eastern | 0.0000544 | 0.0000544 |
| South Asian | 0.00 | 0.00 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF- mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. {ECO:0000269|PubMed:10995748, ECO:0000269|PubMed:15241418, ECO:0000269|PubMed:15588252, ECO:0000269|PubMed:16156666, ECO:0000269|PubMed:16751101, ECO:0000269|PubMed:16862174, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:19218245, ECO:0000269|PubMed:19289081, ECO:0000269|PubMed:9732876, ECO:0000269|PubMed:9892009}.;
- Disease
- DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:16959974}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Loeys-Dietz syndrome 3 (LDS3) [MIM:613795]: An aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Patients with LDS3 also manifest early-onset osteoarthritis. They lack craniosynostosis and mental retardation. {ECO:0000269|PubMed:21217753, ECO:0000269|PubMed:21778426}. Note=The disease is caused by mutations affecting the gene represented in this entry. SMAD3 mutations have been reported to be also associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:21778426). This phenotype is distinguised from LDS3 by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit aneurysms of other arteries, including abdominal aorta, iliac, and/or intracranial arteries (PubMed:21778426), they have been classified as LDS3 by the OMIM resource. {ECO:0000269|PubMed:21778426}.;
- Pathway
- Chronic myeloid leukemia - Homo sapiens (human);Gastric cancer - Homo sapiens (human);Relaxin signaling pathway - Homo sapiens (human);TGF-beta signaling pathway - Homo sapiens (human);Adherens junction - Homo sapiens (human);AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human);Cell cycle - Homo sapiens (human);Endocytosis - Homo sapiens (human);Inflammatory bowel disease (IBD) - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Hippo signaling pathway - Homo sapiens (human);Chagas disease (American trypanosomiasis) - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Th17 cell differentiation - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Hepatitis B - Homo sapiens (human);Wnt signaling pathway - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Pancreatic cancer - Homo sapiens (human);Colorectal cancer - Homo sapiens (human);EGF-Core;WNT-Ncore;NHR;WNT-Core;TGF-Core;Cell Cycle;Androgen receptor signaling pathway;AGE-RAGE pathway;Adipogenesis;Endoderm Differentiation;Mesodermal Commitment Pathway;Extracellular vesicle-mediated signaling in recipient cells;Ovarian Infertility Genes;Hepatitis C and Hepatocellular Carcinoma;TGF-beta Signaling Pathway;Hypothesized Pathways in Pathogenesis of Cardiovascular Disease;Factors and pathways affecting insulin-like growth factor (IGF1)-Akt signaling;TGF-B Signaling in Thyroid Cells for Epithelial-Mesenchymal Transition;Canonical and Non-Canonical TGF-B signaling;Protein alkylation leading to liver fibrosis;Chromosomal and microsatellite instability in colorectal cancer;EMT transition in Colorectal Cancer;TGF-beta Receptor Signaling;Senescence and Autophagy in Cancer;DNA Damage Response (only ATM dependent);Developmental Biology;Disease;RUNX3 regulates CDKN1A transcription;Signal Transduction;Gene expression (Transcription);Signaling by Interleukins;RUNX3 regulates BCL2L11 (BIM) transcription;Transcriptional regulation by RUNX3;cell cycle: g1/s check point;nfkb activation by nontypeable hemophilus influenzae;Generic Transcription Pathway;Signaling by Activin;Cytokine Signaling in Immune system;Alpha6Beta4Integrin;Post-translational protein modification;Metabolism of proteins;RNA Polymerase II Transcription;Immune System;SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription;Downregulation of SMAD2/3:SMAD4 transcriptional activity;AndrogenReceptor;TGF-beta super family signaling pathway canonical;Signaling by NODAL;TGF_beta_Receptor;Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer;EGFR1;tgf beta signaling pathway;Ub-specific processing proteases;Deubiquitination;SMAD2/3 Phosphorylation Motif Mutants in Cancer;SMAD2/3 MH2 Domain Mutants in Cancer;Loss of Function of SMAD2/3 in Cancer;Signaling by TGF-beta Receptor Complex in Cancer;Signaling by TGF-beta Receptor Complex;BMP2 signaling TGF-beta MV;ID;Signaling by TGF-beta family members;BMP signaling Dro;Downregulation of TGF-beta receptor signaling;TGF-beta receptor signaling activates SMADs;Diseases of signal transduction;Validated targets of C-MYC transcriptional repression;Validated targets of C-MYC transcriptional activation;Regulation of Telomerase;Regulation of cytoplasmic and nuclear SMAD2/3 signaling;HIF-1-alpha transcription factor network;Regulation of nuclear SMAD2/3 signaling;TGF-beta receptor signaling;Interleukin-37 signaling;Interleukin-1 family signaling
(Consensus)
Recessive Scores
- pRec
- 0.777
Intolerance Scores
- loftool
- 0.0685
- rvis_EVS
- -0.34
- rvis_percentile_EVS
- 30.37
Haploinsufficiency Scores
- pHI
- 1.00
- hipred
- Y
- hipred_score
- 0.825
- ghis
- 0.526
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Smad3
- Phenotype
- growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype; vision/eye phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system 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; neoplasm; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; immune system phenotype; renal/urinary system phenotype; skeleton phenotype; digestive/alimentary phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan);
Zebrafish Information Network
- Gene name
- smad3b
- Affected structure
- neuron
- Phenotype tag
- abnormal
- Phenotype quality
- degenerate
Gene ontology
- Biological process
- negative regulation of transcription by RNA polymerase II;ureteric bud development;response to hypoxia;in utero embryonic development;mesoderm formation;somitogenesis;liver development;heart looping;osteoblast development;immune system development;regulation of transcription by RNA polymerase II;transcription by RNA polymerase II;activation of cysteine-type endopeptidase activity involved in apoptotic process;immune response;cell cycle arrest;transforming growth factor beta receptor signaling pathway;SMAD protein complex assembly;endoderm development;embryonic pattern specification;positive regulation of gene expression;positive regulation of alkaline phosphatase activity;positive regulation of epithelial to mesenchymal transition;regulation of striated muscle tissue development;protein deubiquitination;regulation of transforming growth factor beta receptor signaling pathway;evasion or tolerance of host defenses by virus;signal transduction involved in regulation of gene expression;negative regulation of cell growth;adrenal gland development;positive regulation of cell migration;positive regulation of bone mineralization;negative regulation of transforming growth factor beta receptor signaling pathway;thyroid gland development;primary miRNA processing;positive regulation of chondrocyte differentiation;positive regulation of interleukin-1 beta production;regulation of transforming growth factor beta2 production;positive regulation of transforming growth factor beta3 production;activin receptor signaling pathway;negative regulation of osteoblast proliferation;nodal signaling pathway;wound healing;T cell activation;negative regulation of protein catabolic process;positive regulation of protein import into nucleus;negative regulation of apoptotic process;cell-cell junction organization;positive regulation of nitric oxide biosynthetic process;negative regulation of fat cell differentiation;negative regulation of osteoblast differentiation;positive regulation of transcription, DNA-templated;negative regulation of mitotic cell cycle;positive regulation of transcription by RNA polymerase II;paraxial mesoderm morphogenesis;developmental growth;embryonic foregut morphogenesis;embryonic cranial skeleton morphogenesis;regulation of epithelial cell proliferation;negative regulation of inflammatory response;regulation of immune response;protein stabilization;positive regulation of positive chemotaxis;positive regulation of DNA-binding transcription factor activity;regulation of binding;negative regulation of cytosolic calcium ion concentration;positive regulation of stress fiber assembly;positive regulation of focal adhesion assembly;pericardium development;transdifferentiation;SMAD protein signal transduction;negative regulation of wound healing;negative regulation of lung blood pressure;lens fiber cell differentiation;cellular response to cytokine stimulus;cellular response to transforming growth factor beta stimulus;positive regulation of canonical Wnt signaling pathway;extrinsic apoptotic signaling pathway;activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway;positive regulation of extracellular matrix assembly;positive regulation of pri-miRNA transcription by RNA polymerase II;negative regulation of cardiac muscle hypertrophy in response to stress
- Cellular component
- nuclear chromatin;nucleus;nuclear inner membrane;nucleoplasm;transcription factor complex;cytoplasm;cytosol;plasma membrane;receptor complex;SMAD protein complex;heteromeric SMAD protein complex
- Molecular function
- RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;proximal promoter sequence-specific DNA binding;RNA polymerase II activating transcription factor binding;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA-binding transcription factor activity;transcription coregulator activity;transforming growth factor beta receptor binding;protein binding;collagen binding;beta-catenin binding;transcription factor binding;zinc ion binding;RNA polymerase II general transcription initiation factor activity;DEAD/H-box RNA helicase binding;protein kinase binding;phosphatase binding;transforming growth factor beta receptor, pathway-specific cytoplasmic mediator activity;chromatin DNA binding;ubiquitin protein ligase binding;mineralocorticoid receptor binding;glucocorticoid receptor binding;enhancer binding;identical protein binding;protein homodimerization activity;ubiquitin binding;bHLH transcription factor binding;sequence-specific DNA binding;transcription regulatory region DNA binding;protein heterodimerization activity;co-SMAD binding;R-SMAD binding;primary miRNA binding