• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
SMAD4 (HGNC:6770) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
SMAD family member 4
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
MADH4
Alias symbols
DPC4
%HI
0.21(Read more about the DECIPHER Haploinsufficiency Index)
pLI
1(Read more about gnomAD pLI score)
LOEUF
0.22(Read more about gnomAD LOEUF score)
Cytoband
18q21.2
Genomic Coordinates
GRCh37/hg19: chr18:48556583-48611412 NCBI Ensembl UCSC
GRCh38/hg38: chr18:51030213-51085042 NCBI Ensembl UCSC
MANE Select Transcript
NM_005359.6 ENST00000342988.8 (Read more about MANE Select)
Function
In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac- specific gene expression. Binds to SMAD binding elements (SBEs) (5'- GTCT/AGAC-3') within BMP response ... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-1866
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
12/16/2020

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Monarch
HI Evidence:
  • PUBMED: 17873119
    Aretz et al., 2007: Mutation and phenotype analysis was used in 80 unrelated patients of whom 65 met the clinical criteria for juvenile polyposis syndrome (typical JPS) and 15 were suspected to have JPS. Of the 17 point mutations identified in SMAD4, 11 were predicted to lead to truncated proteins (5 nonsense, 6 frameshift). Large genomic deletions involving the SMAD4 were found in six (9%) patients with typical JPS. Four exhibited a heterozygous deletion of all SMAD4 probes by MLPA, encompassing the entire SMAD4 gene and the promoter region. One patient had a deletion of coding exons 5-11 and another had a deletion of coding exons 6-11.
  • PUBMED: 20101697
    Callione et al., 2010 identified 15 mutations in 19 patients meeting diagnostic criteria for JPS and hereditary hemorrhagic telangiectasia; 3 small insertions/deletions in exons 8, 9, or 11, predicting to lead to frameshift and premature stop codon in the MH2 domain of the protein. Two protein-truncating mutations in exon 2 and exon 5, and 10 missense mutations in exons 8, 9, or 11. Three were found to be de novo and had no family history of HHT or JPS. Eight had reported family history of either HHT or JP and the available parents did not carry the mutation. Four did not have sufficient family history or parents available for testing.
  • PUBMED: 18823382
    Calva-Cerqueira 2009: DNA was extracted from 102 JPS probands. By MLPA, one proband had deletion of most of SMAD4 and another deletion of the 5' end of SMAD4. Additionally, there were 13 patients with predicted pathogenic mutations (11 truncating, 1 nonsense and 1 splicing). 

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000018.9) (NC_000018.10)