SMAD7
protein-codingSMAD family member 7, the group of SMAD family
Gene summary
The protein encoded by this gene is a nuclear protein that binds the E3 ubiquitin ligase SMURF2. Upon binding, this complex translocates to the cytoplasm, where it interacts with TGF-beta receptor type-1 (TGFBR1), leading to the degradation of both the encoded protein and TGFBR1. Expression of this gene is induced by TGFBR1. Variations in this gene are a cause of susceptibility to colorectal cancer type 3 (CRCS3). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]
- MADH8
- MADH7
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~31.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0012820
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0005453
Submitter: ClinGen
*SMAD7* was first reported in relation to autosomal dominant congenital heart disease in 2013 (Wang et al. 2013, PMID: 24039762). A missense variant reported in an individual with CHD was included in this curation (PMID: 24039762). There are more variants reported in individuals with CHD in two publications, all of which were synonymous variants that were not scored due to either low SpliceAI scores or high minor allele frequency (>0.00001) on gnomAD v.4 (PMID: 24039762, 28078173). This gene-disease relationship is also supported by expression data in mouse embryos and 2 mouse models showing heart defects (PMID: 18952608). In summary, there is limited evidence supporting the relationship between *SMAD7* and autosomal dominant congenital heart disease. 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 Congenital Heart Disease GCEP on the meeting date May 13th, 2024 (SOP Version 10).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SMAD7 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005904.4. 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 | 5 | 5 | 11 | ||
| missense | 56 | 5 | 61 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 57 | 10 | 5 | 72 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005895.1 | 4 | MANE Select | |
| Ensembl | ENSP00000262158.2 | 4 | MANE Select | |
| RefSeq | NP_001177750.1 | 4 | Standard | |
| RefSeq | NP_001177751.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| smad7 | Danio rerio | Structure: muscle Quality: hypoplastic abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- TGF-beta signaling pathway - Homo sapiens (human)
- Hippo signaling pathway - Homo sapiens (human)
- TGF-Core
- EGF-Ncore
- Transcriptional activity of SMAD2-SMAD3-SMAD4 heterotrimer
Biological Process
- negative regulation of transcription by RNA polymerase II
- ureteric bud development
- negative regulation of T cell cytokine production
- transforming growth factor beta receptor signaling pathway
- regulation of epithelial to mesenchymal transition
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- protein binding
- collagen binding
- beta-catenin binding
- transforming growth factor beta receptor, inhibitory cytoplasmic mediator activity
Cellular Component
- fibrillar center
- nucleus
- nucleoplasm
- transcription factor complex
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000262158
- Coding exons
- 4
- Length
- 30859
- Individuals with no LoFs
- 125744
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125748
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.65 | 154 | 224 | 0.689 | 0.0000126 | 2685 |
| Missense (PolyPhen) | 52 | 99.23 | 0.52403 | 1148 | ||
| Synonymous | -1.97 | 131 | 105 | 1.24 | 0.00000648 | 901 |
| Loss of Function | 2.91 | 3 | 15.3 | 0.196 | 6.67e-7 | 177 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00012 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000090 | 0.0000088 | rare |
| South Asian | 0.000037 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit TGF-beta (Transforming growth factor) and activin signaling by associating with their receptors thus preventing SMAD2 access. Functions as an adapter to recruit SMURF2 to the TGF-beta receptor complex. Also acts by recruiting the PPP1R15A- PP1 complex to TGFBR1, which promotes its dephosphorylation. 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:11163210, ECO:0000269|PubMed:12023024, ECO:0000269|PubMed:14718519, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:9892009}.;
- Disease
- DISEASE: Colorectal cancer 3 (CRCS3) [MIM:612229]: 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:17934461}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.363
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |