SMAD9

SMAD family member 9, the group of SMAD family

Basic information

Region (hg38): 13:36844830-36920765

Previous symbols: [ "MADH6", "MADH9" ]

Links

ENSG00000120693 ∙ NCBI:4093 ∙ OMIM:603295 ∙ HGNC:6774 ∙ Uniprot:O15198 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• heritable pulmonary arterial hypertension (Supportive), mode of inheritance: AD
• pulmonary hypertension, primary, 2 (Strong), mode of inheritance: AD
• pulmonary hypertension, primary, 2 (Limited), mode of inheritance: AD
• pulmonary arterial hypertension (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pulmonary hypertension, primary 2	AD	Cardiovascular; Pulmonary	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	Cardiovascular; Pulmonary	19211612

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SMAD9 gene.

• Pulmonary hypertension, primary, 2 (74 variants)
• not provided (36 variants)
• Pulmonary hypertension, primary, 1 (27 variants)
• Inborn genetic diseases (16 variants)
• not specified (10 variants)
• SMAD9-related condition (2 variants)
• Pulmonary arterial hypertension associated with congenital heart disease (2 variants)
• Lung cancer (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SMAD9 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				25	5	30
missense			39	3	1	43
nonsense	3	1				4
start loss						0
frameshift		2	2			4
inframe indel			1			1
splice donor/acceptor (+/-2bp)		1				1
splice region				2		2
non coding			24	13	16	53
Total	3	4	66	41	22

Highest pathogenic variant AF is 0.0000855

Variants in SMAD9

This is a list of pathogenic ClinVar variants found in the SMAD9 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
13-36845085-AT-A		Pulmonary hypertension, primary, 1	Uncertain significance (Jun 14, 2016)
13-36845100-ATG-A		Pulmonary hypertension, primary, 1	Uncertain significance (Jun 14, 2016)
13-36845100-ATGTG-A		Pulmonary hypertension, primary, 1	Benign (Jun 14, 2016)
13-36845110-GTGTGTA-G		Pulmonary hypertension, primary, 1	Uncertain significance (Jun 14, 2016)
13-36845112-GTGTATA-G		Pulmonary hypertension, primary, 1	Uncertain significance (Jun 14, 2016)
13-36845114-GTA-G		Pulmonary hypertension, primary, 1	Uncertain significance (Jun 14, 2016)
13-36845114-GTATA-G		Pulmonary hypertension, primary, 1	Uncertain significance (Jun 14, 2016)
13-36845114-G-GTA		Pulmonary hypertension, primary, 1	Uncertain significance (Jun 14, 2016)
13-36846473-CA-C		Pulmonary hypertension, primary, 1	Uncertain significance (Jun 14, 2016)
13-36846473-CAA-C		Pulmonary hypertension, primary, 1	Uncertain significance (Jun 14, 2016)
13-36846494-AAAG-A		Pulmonary hypertension, primary, 1	Uncertain significance (Jun 14, 2016)
13-36846495-AAG-A		Pulmonary hypertension, primary, 1	Uncertain significance (Jun 14, 2016)
13-36846496-AG-A		Pulmonary hypertension, primary, 1	Uncertain significance (Jun 14, 2016)
13-36848005-ACT-A		Pulmonary hypertension, primary, 1	Uncertain significance (Jun 14, 2016)
13-36848008-CTG-C		Pulmonary hypertension, primary, 1	Uncertain significance (Jun 14, 2016)
13-36848223-GACATC-G		Pulmonary hypertension, primary, 1	Uncertain significance (Jun 14, 2016)
13-36848374-GCTGT-G		Pulmonary hypertension, primary, 1	Uncertain significance (Jun 14, 2016)
13-36848378-T-C			Benign (Nov 08, 2018)
13-36848476-T-G			Benign (Nov 08, 2018)
13-36848580-CAT-C		Pulmonary hypertension, primary, 1	Uncertain significance (Jun 14, 2016)
13-36848629-C-T			Benign (Dec 24, 2018)
13-36848745-T-G		Pulmonary hypertension, primary, 2	Likely benign (May 02, 2023)
13-36848798-G-A		SMAD9-related disorder	Uncertain significance (Apr 06, 2023)
13-36848895-G-A			Benign (Jun 14, 2018)
13-36849084-C-G			Likely benign (Jul 11, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SMAD9	protein_coding	protein_coding	ENST00000379826	6	75935

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000644	0.978	125713	0	35	125748	0.000139

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.522	248	272	0.911	0.0000168	3056
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000569	0.000568
Ashkenazi Jewish	0.00	0.00
East Asian	0.000272	0.000272
Finnish	0.0000929	0.0000924
European (Non-Finnish)	0.000106	0.000105
Middle Eastern	0.000272	0.000272
South Asian	0.0000653	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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;TGF-beta Receptor Signaling;Signal Transduction;TGF-beta super family signaling pathway canonical;BMP receptor signaling;BMP Signalling Pathway;BMP2 signaling TGF-beta MV;Signaling by BMP;Signaling by TGF-beta family members;BMP signaling Dro;ALK1 signaling events;ALK2 signaling events (Consensus)

Recessive Scores

• pRec: 0.185

Intolerance Scores

• loftool: 0.151
• rvis_EVS: -0.78
• rvis_percentile_EVS: 12.88

Haploinsufficiency Scores

• pHI: 0.979
• hipred: Y
• hipred_score: 0.800
• ghis: 0.587

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.852

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Smad9
• Phenotype: skeleton phenotype; immune system 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); limbs/digits/tail phenotype; neoplasm; reproductive 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); normal 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); respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; craniofacial phenotype; muscle phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: smad9
• Affected structure: macrophage
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• 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
• Cellular component: nucleus;nucleoplasm;transcription factor complex;cytoplasm;cytosol;SMAD protein complex
• 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