GeneBe

SMAD6

protein-coding

SMAD family member 6, the group of SMAD family

Gene summary

The protein encoded by this gene belongs to the SMAD family of proteins, which are related to Drosophila 'mothers against decapentaplegic' (Mad) and C. elegans Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein functions in the negative regulation of BMP and TGF-beta/activin-signalling. Multiple transcript variants have been found for this gene.[provided by RefSeq, Sep 2014]

Previous symbols:
  • MADH7
  • MADH6

MANE transcript

NM_005585.5

Inheritance

AD, AR

ClinVar variants

P:120U:827B:363

Top phenotype

Aortic valve disease 2

gnomAD constraint

pLI —, LoF o/e 1.97

Max pathogenic AF

—

Genomic locus

chr15:66,702,236-66,782,849

External References & Databases

Ensembl (ENSG00000137834)NCBI Gene (4091)OMIM (602931)HGNC:6772GenCCUniProt (O43541)AlphaFoldClinVar (SMAD6)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~80.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

craniosynostosis 7MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0044315

Submitter: Ambry Genetics

radioulnar synostosis, nonsyndromic, susceptibility toSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100183

Submitter: Ambry Genetics

SMAD6-related diseaseDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0700324

Submitter: ClinGen

SMAD6 was first reported in relation to autosomal dominant SMAD6-related disease in 2016 (Timberlake et al., PMID: 27606499). SMAD6-related disease is the presentation of craniosynostosis with congenital heart defects and/or radioulnar synostosis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern. Variants in SMAD6 causing aortic valve disease, craniosynostosis, and radioulnar synostosis were located throughout the gene. Reports have also shown various syndromic presentations of SMAD6 variants. Therefore, the following disease entities have been lumped into one disease entity, Aortic Valve Disease 2 (OMIM:614823), Craniosynostosis 7 (OMIM:617439), and Radioulnar Synostosis (OMIM:179300). 28 variants (missense, nonsense, and frameshift) that have been reported in 28 probands in 3 publications (PMIDs: 34953066, 32499606, 27606499) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by animal models and expression studies (PMIDs: 21681813, 10655064). SMAD6 was found to be expressed in developing cardiac tissue and bones, and mice deficient in SMAD6 were found to exhibit phenotypes similar to aortic valve disorder and craniosynostosis. In summary, SMAD6 is definitively associated with autosomal dominant SMAD6-related disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date 06/15/2023 (SOP Version 9).

congenital heart defects, multiple typesLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0000119

Submitter: Ambry Genetics

familial bicuspid aortic valveSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007194

Submitter: Orphanet

craniosynostosis 7LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0044315

Submitter: G2P

aortic valve disease 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013902

Submitter: PanelApp Australia

congenital radioulnar synostosisLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0017985

Submitter: Ambry Genetics

craniosynostosis 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0044315

Submitter: PanelApp Australia

craniosynostosis 7LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0044315

Submitter: Labcorp Genetics (formerly Invitae)

aortic valve disease 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013902

Submitter: Ambry Genetics

radioulnar synostosis, nonsyndromic, susceptibility toSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100183

Submitter: PanelApp Australia

aortic valve disease 2LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013902

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Aortic valve disease 2AD

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: 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

Refs: 22275001; 27606499; 31138930Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SMAD6 variants in ClinVar

28 Conditions Cataloged
Aortic valve disease 2Total: 870
Inborn genetic diseasesTotal: 632
not providedTotal: 212
not specifiedTotal: 101
Radioulnar synostosisTotal: 72
SMAD6-related diseaseTotal: 67
Craniosynostosis 7Total: 33
Radioulnar synostosis, nonsyndromic, susceptibility toTotal: 22

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005585.5. 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.

EffectPLPVUSLBBSum
synonymous
326
clinvar
1
clinvar
 327
missense
4
clinvar
11
clinvar
687
clinvar
35
clinvar
1
clinvar
 738
nonsense
13
clinvar
31
clinvar
36
clinvar
 80
start loss
1
clinvar
5
clinvar
 6
frameshift
19
clinvar
39
clinvar
88
clinvar
 146
splice donor/acceptor (+/-2bp)
1
clinvar
1
clinvar
11
clinvar
 13
Total378382736121310

Highest pathogenic variant AF is 0.000016379667

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_005585.5RefSeqNP_005576.34MANE Select
ENST00000288840.10EnsemblENSP00000288840.54MANE Select
ENST00000557916.5EnsemblENSP00000452955.14Standard
ENST00000558937.1EnsemblENSP00000452694.13Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • 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

Biological Process

  • ureteric bud development
  • outflow tract septum morphogenesis
  • aortic valve morphogenesis
  • mitral valve morphogenesis
  • pulmonary valve morphogenesis

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

Cellular Component

  • nucleus
  • transcription factor complex
  • cytoplasm
  • Golgi apparatus
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000288840
Coding exons
4
Length
79773
Individuals with no LoFs
125697
Homozygous LoFs
0
Heterozygous LoFs
51
Defined
125748
p
0.000203
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.5922492241.110.00001523019
Missense (PolyPhen)97101.180.958731142
Synonymous0.3721081130.9550.000009051080
Loss of Function-3.072311.71.975.85e-7155

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000290.00025rare
Latino/Admixed American0.000150.00014rare
Ashkenazi Jewish00.0absent
East Asian0.000220.00022rare
Finnish0.000240.00018rare
European (Non-Finnish)0.000210.00020rare
South Asian0.000330.00029rare
Other0.000340.00033rare

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec
0.260

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.998

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.