SMAD1
protein-codingSMAD family member 1, the group of SMAD family
Gene summary
The protein encoded by this gene belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein mediates the signals of the bone morphogenetic proteins (BMPs), which are involved in a range of biological activities including cell growth, apoptosis, morphogenesis, development and immune responses. In response to BMP ligands, this protein can be phosphorylated and activated by the BMP receptor kinase. The phosphorylated form of this protein forms a complex with SMAD4, which is important for its function in the transcription regulation. This protein is a target for SMAD-specific E3 ubiquitin ligases, such as SMURF1 and SMURF2, and undergoes ubiquitination and proteasome-mediated degradation. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]
- MADH1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~78.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0005453
Submitter: ClinGen
SMAD1 was first reported in relation to autosomal dominant congenital heart disease in 2020 (Lago-Docampo et al; PMID: 32934261). Six variants (missense, nonsense, frameshift) that have been reported in thirteen probands in four publications (PMIDs: 30578397, 32934261, 33007923, 35281600) are included in this curation. However, only two variants (nonsense, frameshift) were scored (PMIDs: 32934261, 35281600) as the other variants were only seen in isolated idiopathic pulmonary arterial hypertension cases and/or were too frequent in population databases. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (NCBI fetal expression data). In summary, there is limited evidence to support this gene-disease relationship. 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 5/13/2024 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0015924
Submitter: ClinGen
SMAD1 was first reported in relation to autosomal dominant pulmonary arterial hypertension (PAH) in 2011 (Nasim et al., PMID:21898662) in a cohort of PAH patients without BMPR2 variants and screened for variants in the candidate SMAD genes. One missense variant with MAF <=0.0001 was identified. In total, two SMAD1 missense variants with MAF <=0.0001 have been reported in two HPAH/IPAH probands in 2 publications (PMIDs: 21898662, 33007923). Experimental evidence for a relationship between SMAD1 and PAH is supported by biochemical function from three publications (PMIDs: 18367643, 23478097, 21898662) and in conditional kock out mice in which a subset of KO mice developed pulmonary hypertension. However, the gene-disease relationship betwen SMAD1 and PAH is classified as disputed due to insufficient genetic evidence over multiple years of research. This classification was approved by the ClinGen PH Gene Curation Expert Panel on 8/30/2022 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0015924
Submitter: PanelApp Australia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SMAD1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005900.3. 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 | 1 | 2 | |||
| missense | 33 | 33 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 0 | 36 | 1 | 0 | 37 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005891.1 | 6 | MANE Select | |
| Ensembl | ENSP00000305769.4 | 6 | MANE Select | |
| RefSeq | NP_001003688.1 | 6 | Standard | |
| RefSeq | NP_001341740.1 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| smad1 | Danio rerio | Structure: nucleate erythrocyte Quality: increased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- TGF-beta signaling pathway - Homo sapiens (human)
- Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
- Hippo signaling pathway - Homo sapiens (human)
- Transcriptional misregulation in cancer - Homo sapiens (human)
- TGF-Core
Biological Process
- MAPK cascade
- ureteric bud development
- mesodermal cell fate commitment
- osteoblast fate commitment
- inflammatory response
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- DNA-binding transcription factor activity
- protein binding
Cellular Component
- nucleus
- nuclear inner membrane
- nucleoplasm
- transcription factor complex
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000515385
- Coding exons
- 6
- Length
- 76886
- Individuals with no LoFs
- 125563
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 125564
- p
- 0.00000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.28 | 159 | 263 | 0.604 | 0.0000143 | 3096 |
| Missense (PolyPhen) | 41 | 107.5 | 0.38139 | 1282 | ||
| Synonymous | -0.678 | 103 | 94.6 | 1.09 | 0.00000520 | 875 |
| Loss of Function | 3.69 | 1 | 17.8 | 0.0563 | 7.57e-7 | 223 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| 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) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD1 is a receptor-regulated SMAD (R-SMAD). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1. May act synergistically with SMAD4 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. {ECO:0000269|PubMed:12097147}.;
- Disease
- DISEASE: Note=SMAD1 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs. {ECO:0000269|PubMed:21898662}.;
Recessive Scores
- pRec
- 0.230
Intolerance Scores
- LoFtool
- 0.0253
- RVIS EVS
- -0.41
- RVIS percentile EVS
- 26.23
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.998
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |