SMAD6

SMAD family member 6, the group of SMAD family

Basic information

Region (hg38): 15:66702236-66782849

Previous symbols: [ "MADH7", "MADH6" ]

Links

ENSG00000137834 ∙ NCBI:4091 ∙ OMIM:602931 ∙ HGNC:6772 ∙ Uniprot:O43541 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• aortic valve disease 2 (Moderate), mode of inheritance: AD
• craniosynostosis 7 (Strong), mode of inheritance: AD
• congenital radioulnar synostosis (Supportive), mode of inheritance: Unknown
• familial bicuspid aortic valve (Supportive), mode of inheritance: AD
• congenital radioulnar synostosis (Limited), mode of inheritance: AR
• aortic valve disease 2 (Moderate), mode of inheritance: AD
• craniosynostosis 7 (Moderate), mode of inheritance: AD
• radioulnar synostosis, nonsyndromic, susceptibility to (Strong), mode of inheritance: AD
• aortic valve disease 2 (Limited), mode of inheritance: Unknown
• craniosynostosis 7 (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Aortic valve disease 2	AD	Cardiovascular	Individuals may manifest with sequelae of cardiovascular anomalies including bicuspid, aortic valve, aortic stenosis, and aortic coarctation, and awareness may allow early detection and medical/surgical management, which may ameliorate morbidity and mortality	Cardiovascular; Craniofacial; Musculoskeletal; Neurologic	22275001; 27606499; 31138930

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SMAD6 gene.

• not provided (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SMAD6 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			2	242	3	247
missense	1	2	436	12	1	452
nonsense		6	25			31
start loss			5			5
frameshift		7	45			52
inframe indel			14			14
splice donor/acceptor (+/-2bp)	1		8			9
splice region			5	6		11
non coding				15	13	28
Total	2	15	535	269	17

Variants in SMAD6

This is a list of pathogenic ClinVar variants found in the SMAD6 region.

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

Position	Type	Phenotype	Significance	ClinVar
15-66702492-C-T			Benign (Sep 04, 2018)
15-66702985-G-A			Benign (Sep 04, 2018)
15-66703215-C-T			Likely benign (Jul 29, 2019)
15-66703257-GTATGT-G		SMAD6-related disorder	Uncertain significance (Sep 14, 2023)
15-66703259-A-G		Aortic valve disease 2	Uncertain significance (Mar 16, 2022)
15-66703260-T-A		Aortic valve disease 2	Uncertain significance (Oct 17, 2022)
15-66703260-T-C		Polydactyly;Radioulnar synostosis • Aortic valve disease 2	Conflicting classifications of pathogenicity (Sep 11, 2024)
15-66703260-T-G		Aortic valve disease 2	Uncertain significance (Jul 02, 2017)
15-66703260-T-TG		Radioulnar synostosis	Pathogenic (Jun 20, 2020)
15-66703262-T-G		Inborn genetic diseases	Uncertain significance (Dec 17, 2023)
15-66703266-G-A		Aortic valve disease 2 • Inborn genetic diseases	Uncertain significance (Mar 11, 2024)
15-66703267-G-T		Inborn genetic diseases	Uncertain significance (Nov 30, 2022)
15-66703270-C-T		Aortic valve disease 2	Likely benign (May 29, 2022)
15-66703274-C-T		Aortic valve disease 2	Uncertain significance (Jan 06, 2024)
15-66703274-C-CGCTCG		Aortic valve disease 2	Uncertain significance (Dec 19, 2023)
15-66703276-C-G		Aortic valve disease 2	Likely benign (Mar 22, 2023)
15-66703277-T-C		Aortic valve disease 2	Uncertain significance (Aug 29, 2021)
15-66703278-C-A		Aortic valve disease 2	Uncertain significance (Oct 05, 2023)
15-66703278-CG-C		Radioulnar synostosis	Pathogenic (Jun 20, 2020)
15-66703279-G-A		Aortic valve disease 2	Likely benign (Aug 22, 2022)
15-66703283-C-G		Inborn genetic diseases • Aortic valve disease 2	Uncertain significance (Jan 03, 2024)
15-66703283-C-T		Aortic valve disease 2 • Inborn genetic diseases	Likely benign (Jun 23, 2023)
15-66703284-T-A		Inborn genetic diseases	Uncertain significance (Apr 07, 2023)
15-66703284-T-C		Aortic valve disease 2	Uncertain significance (Aug 09, 2022)
15-66703286-G-T		Aortic valve disease 2	Uncertain significance (Jan 12, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SMAD6	protein_coding	protein_coding	ENST00000288840	4	79773

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.63e-20	0.0000244	125697	0	51	125748	0.000203

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.592	249	224	1.11	0.0000152	3019
Missense in Polyphen		97	101.18	0.95873		1142
Synonymous	0.372	108	113	0.955	0.00000905	1080
Loss of Function	-3.07	23	11.7	1.97	5.85e-7	155

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000437	0.000393
Ashkenazi Jewish	0.00	0.00
East Asian	0.000220	0.000217
Finnish	0.000240	0.000185
European (Non-Finnish)	0.000213	0.000202
Middle Eastern	0.000220	0.000217
South Asian	0.000330	0.000294
Other	0.000339	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Acts as a mediator of TGF-beta and BMP antiflammatory activity. Suppresses IL1R-TLR signaling through its direct interaction with PEL1, preventing NF-kappa-B activation, nuclear transport and NF-kappa-B-mediated expression of proinflammatory genes. May block the BMP-SMAD1 signaling pathway by competing with SMAD4 for receptor-activated SMAD1-binding. Binds to regulatory elements in target promoter regions. {ECO:0000269|PubMed:16491121, ECO:0000269|PubMed:16951688, ECO:0000269|PubMed:9436979}.
• Disease: DISEASE: Aortic valve disease 2 (AOVD2) [MIM:614823]: A common defect in the aortic valve in which two rather than three leaflets are present. It is often associated with aortic valve calcification, stenosis and insufficiency. In extreme cases, the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome. {ECO:0000269|PubMed:22275001}. Note=The disease is caused by mutations affecting the gene represented in this entry. SMAD6 variants may contribute to increased risk of congenital cardiovascular malformations (CVM). CVM is a major cause of mortality and morbidity in childhood. In most sporadic cases that cannot be attributed to particular malformation syndromes or teratogenic exposures, there remains a substantial excess familial risk, indicating a significant genetic contribution to disease susceptibility (PubMed:22275001). {ECO:0000269|PubMed:22275001}.; DISEASE: Craniosynostosis 7 (CRS7) [MIM:617439]: A form of craniosynostosis, a primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability. {ECO:0000269|PubMed:27606499}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Rare heterozygous SMAD6 variants are strongly associated with non-syndromic midline craniosynostosis and confer a very high risk for disease development, in the presence of a common risk allele (rs1884302) near the BMP2 locus. {ECO:0000269|PubMed:27606499}.
• Pathway: TGF-beta signaling pathway - Homo sapiens (human);TGF-Ncore;EGF-Ncore;Bone Morphogenic Protein (BMP) Signalling and Regulation;Regulation of toll-like receptor signaling pathway;Mesodermal Commitment Pathway;ESC Pluripotency Pathways;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;RNA Polymerase II Transcription;BMP2 signaling TAK1;TGF-beta super family signaling pathway canonical;TGF_beta_Receptor;BMP receptor signaling;BMP Signalling Pathway;BMP2 signaling TGF-beta MV;Signaling by BMP;Signaling by TGF-beta family members (Consensus)

Recessive Scores

• pRec: 0.260

Haploinsufficiency Scores

• pHI: 0.951
• hipred: Y
• hipred_score: 0.637
• ghis: 0.609

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: Smad6
• 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); 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); homeostasis/metabolism phenotype; muscle phenotype

Gene ontology

• Biological process: ureteric bud development;outflow tract septum morphogenesis;aortic valve morphogenesis;mitral valve morphogenesis;pulmonary valve morphogenesis;ventricular septum development;immune response;transforming growth factor beta receptor signaling pathway;zygotic specification of dorsal/ventral axis;negative regulation of cell population proliferation;negative regulation of SMAD protein complex assembly;negative regulation of ossification;BMP signaling pathway;negative regulation of transforming growth factor beta receptor signaling pathway;negative regulation of BMP signaling pathway;cell-substrate adhesion;response to laminar fluid shear stress;aorta development;negative regulation of apoptotic process;response to estrogen;fat cell differentiation;negative regulation of osteoblast differentiation;negative regulation of pathway-restricted SMAD protein phosphorylation;coronary vasculature development;positive regulation of pri-miRNA transcription by RNA polymerase II
• Cellular component: nucleus;transcription factor complex;cytoplasm;Golgi apparatus;cytosol;nuclear body;protein-containing complex
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;chromatin binding;protein binding;transforming growth factor beta receptor, inhibitory cytoplasmic mediator activity;ubiquitin protein ligase binding;type I transforming growth factor beta receptor binding;identical protein binding;transcription regulatory region DNA binding;metal ion binding;co-SMAD binding;I-SMAD binding;R-SMAD binding;type I activin receptor binding