SMAD9
protein-codingSMAD family member 9, the group of SMAD family
Gene summary
The protein encoded by this gene is a member of the SMAD family, which transduces signals from TGF-beta family members. The encoded protein is activated by bone morphogenetic proteins and interacts with SMAD4. Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]
- MADH6
- MADH9
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~76.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014134
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0015924
Submitter: ClinGen
SMAD9 was first reported in relation to autosomal dominant pulmonary arterial hypertension in 2009 (Shintani et al., PMID: 19211612). At least 15 variants (e.g. missense, in-frame indel, nonsense, frameshift, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data, including protein interaction, functional alteration in non-patient and patient cells and rescue in patient cells. Summary of case-level data: 7.3 points Variants in this gene have been reported in at least 15 probands in 5 publications (PMIDs: 19211612, 21920918, 29650961, 31727138, 30578397). The mechanism for disease is haploinsufficiency. Summary of experimental evidence: 4.5 points. The gene-disease association is supported by data demonstrating protein interaction, functional alteration in non-patient and patient cells and rescue in patient cells (PMIDs: 19211612, 21920918). The evidence supporting this gene-disease relationship has been replicated over more than 10 years. In summary, SMAD9 is definitively associated with autosomal dominant pulmonary arterial hypertension. This classification was approved by the ClinGen PH Gene Curation Expert Panel on May 12, 2021.
Inheritance Pattern: AD
Disease ID:MONDO:0014134
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014134
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0017148
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Pulmonary
Intervention: Cardiovascular; Pulmonary
Rationale: While prognosis is overall poor, medical therapy (eg, with, oral calcium antagonists, anticoagulants, epoprostenol) may be beneficial, though heart/lung transplantation may be required; Control of complications may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SMAD9 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001127217.3. 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 | 75 | 4 | 80 | ||
| missense | 117 | 12 | 1 | 130 | ||
| nonsense | 6 | 6 | 2 | 14 | ||
| start loss | 1 | 1 | ||||
| frameshift | 7 | 12 | 1 | 20 | ||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 13 | 21 | 122 | 87 | 5 | 248 |
Highest pathogenic variant AF is 0.0001803598
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001120689.1 | 6 | MANE Select | |
| Ensembl | ENSP00000369154.4 | 6 | MANE Select | |
| RefSeq | NP_001365550.1 | 5 | Standard | |
| RefSeq | NP_005896.1 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| smad9 | Danio rerio | Structure: macrophage Quality: decreased 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)
- Differentiation of white and brown adipocyte
- BMP2-WNT4-FOXO1 Pathway in Human Primary Endometrial Stromal Cell Differentiation
- ESC Pluripotency Pathways
Biological Process
- transforming growth factor beta receptor signaling pathway
- BMP signaling pathway
- SMAD protein signal transduction
- cellular response to BMP stimulus
- positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA binding
- protein binding
- transforming growth factor beta receptor, pathway-specific cytoplasmic mediator activity
- metal ion binding
Cellular Component
- nucleus
- nucleoplasm
- transcription factor complex
- cytoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000379826
- Coding exons
- 6
- Length
- 75935
- Individuals with no LoFs
- 125713
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 35
- Defined
- 125748
- p
- 0.000139
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.522 | 248 | 272 | 0.911 | 0.0000168 | 3056 |
| Missense (PolyPhen) | 108 | 131.13 | 0.82359 | 1476 | ||
| Synonymous | -1.03 | 127 | 113 | 1.12 | 0.00000796 | 925 |
| Loss of Function | 2.06 | 10 | 19.9 | 0.502 | 0.00000103 | 225 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00031 | 0.00031 | rare |
| Latino/Admixed American | 0.00026 | 0.00026 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00027 | 0.00027 | rare |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.00011 | 0.00011 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD9 is a receptor-regulated SMAD (R-SMAD).;
- Disease
- DISEASE: Pulmonary hypertension, primary, 2 (PPH2) [MIM:615342]: A rare 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}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.185
Intolerance Scores
- LoFtool
- 0.151
- RVIS EVS
- -0.78
- RVIS percentile EVS
- 12.88
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.852
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |