SMAD1

SMAD family member 1, the group of SMAD family

Basic information

Region (hg38): 4:145481193-145559176

Previous symbols: [ "MADH1" ]

Links

ENSG00000170365 ∙ NCBI:4086 ∙ OMIM:601595 ∙ HGNC:6767 ∙ Uniprot:Q15797 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• pulmonary arterial hypertension (Disputed Evidence), mode of inheritance: AD

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SMAD1 gene.

• not provided (22 variants)
• Inborn genetic diseases (9 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SMAD1 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						0
missense			9			9
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding				2	20	22
Total	0	0	9	2	20

Variants in SMAD1

This is a list of pathogenic ClinVar variants found in the SMAD1 region.

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

Position	Type	Phenotype	Significance	ClinVar
4-145514438-G-A			Likely benign (Feb 12, 2022)
4-145514621-T-C		Variant of unknown significance • Pulmonary hypertension, primary, 1	Uncertain significance (Dec 01, 2011)
4-145514795-C-T		not specified	Uncertain significance (May 15, 2023)
4-145514916-T-A		not specified	Uncertain significance (Jul 19, 2022)
4-145514936-G-A		not specified	Uncertain significance (Jul 13, 2022)
4-145515134-CTG-C			Benign (Oct 20, 2020)
4-145515134-CTGTG-C			Benign (May 24, 2021)
4-145515134-CTGTGTGTG-C			Benign (May 20, 2021)
4-145515134-C-CTG			Benign (May 19, 2021)
4-145515134-C-CTGTG			Benign (Sep 29, 2019)
4-145515134-C-CTGTGTG			Benign (Sep 29, 2019)
4-145515170-G-GTGTGTC			Likely benign (Nov 20, 2020)
4-145515199-A-G			Benign (Jul 12, 2019)
4-145539951-C-T		not specified	Uncertain significance (Jul 16, 2021)
4-145540037-C-T		not specified	Uncertain significance (Feb 09, 2023)
4-145540284-A-G			Benign (Sep 15, 2020)
4-145540382-C-T			Benign (Jul 12, 2019)
4-145542594-C-T		not specified	Uncertain significance (Jan 08, 2024)
4-145542675-T-C		not specified	Uncertain significance (Aug 09, 2021)
4-145542814-T-C			Benign (Sep 04, 2018)
4-145546736-A-C		not specified	Uncertain significance (Nov 29, 2023)
4-145553690-C-T			Benign (May 21, 2021)
4-145553802-T-G		not specified	Uncertain significance (May 24, 2023)
4-145553894-A-G		not specified	Uncertain significance (Dec 13, 2021)
4-145553989-G-A		SMAD1-related disorder	Likely benign (Feb 27, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SMAD1	protein_coding	protein_coding	ENST00000515385	6	76886

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.988	0.0120	125563	0	1	125564	0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.28	159	263	0.604	0.0000143	3096
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000881	0.00000881
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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}.
• Pathway: 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;Bone Morphogenic Protein (BMP) Signalling and Regulation;Angiogenesis;Heart Development;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in squamous cell - TarBase;Neural Crest Differentiation;Mesodermal Commitment Pathway;Differentiation of white and brown adipocyte;BMP2-WNT4-FOXO1 Pathway in Human Primary Endometrial Stromal Cell Differentiation;BMP Signaling Pathway in Eyelid Development;ESC Pluripotency Pathways;Protein alkylation leading to liver fibrosis;TGF-beta Receptor Signaling;RUNX2 regulates bone development;Transcriptional regulation by RUNX2;Signal Transduction;Gene expression (Transcription);alk in cardiac myocytes;ctcf: first multivalent nuclear factor;Generic Transcription Pathway;Post-translational protein modification;Metabolism of proteins;RNA Polymerase II Transcription;TGF-beta super family signaling pathway canonical;BMP receptor signaling;ErbB1 downstream signaling;BMP Signalling Pathway;Ub-specific processing proteases;LIF signaling;Deubiquitination;Wnt;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: 0.230

Intolerance Scores

• loftool: 0.0253
• rvis_EVS: -0.41
• rvis_percentile_EVS: 26.23

Haploinsufficiency Scores

• pHI: 0.953
• hipred: Y
• hipred_score: 0.860
• ghis: 0.622

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.998

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Smad1
• Phenotype: endocrine/exocrine gland phenotype; growth/size/body region phenotype; homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype; muscle phenotype; digestive/alimentary 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); neoplasm; 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); normal 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; embryo phenotype; skeleton phenotype

Zebrafish Information Network

• Gene name: smad1
• Affected structure: nucleate erythrocyte
• Phenotype tag: abnormal
• Phenotype quality: increased amount

Gene ontology

• Biological process: MAPK cascade;ureteric bud development;mesodermal cell fate commitment;osteoblast fate commitment;inflammatory response;signal transduction;transforming growth factor beta receptor signaling pathway;SMAD protein complex assembly;gamete generation;negative regulation of cell population proliferation;embryonic pattern specification;positive regulation of gene expression;protein deubiquitination;BMP signaling pathway;midbrain development;hindbrain development;primary miRNA processing;homeostatic process;positive regulation of osteoblast differentiation;positive regulation of transcription by RNA polymerase II;cartilage development;cardiac muscle cell proliferation;bone development;SMAD protein signal transduction;positive regulation of cartilage development;cellular response to organic cyclic compound;positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus;positive regulation of pri-miRNA transcription by RNA polymerase II;positive regulation of sprouting angiogenesis
• Cellular component: nucleus;nuclear inner membrane;nucleoplasm;transcription factor complex;cytoplasm;cytosol;integral component of membrane;protein-containing complex;SMAD protein complex
• 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;DEAD/H-box RNA helicase binding;protein kinase binding;transforming growth factor beta receptor, pathway-specific cytoplasmic mediator activity;identical protein binding;protein homodimerization activity;metal ion binding;protein heterodimerization activity;co-SMAD binding;I-SMAD binding;primary miRNA binding