18-51047093-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005359.6(SMAD4):​c.47G>A​(p.Cys16Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C16S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SMAD4
NM_005359.6 missense

Scores

14
4
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.97

Publications

0 publications found
Variant links:
Genes affected
SMAD4 (HGNC:6770): (SMAD family member 4) This gene encodes a member of the Smad family of signal transduction proteins. Smad proteins are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor (TGF)-beta signaling. The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and recognizes an 8-bp palindromic sequence (GTCTAGAC) called the Smad-binding element (SBE). The protein acts as a tumor suppressor and inhibits epithelial cell proliferation. It may also have an inhibitory effect on tumors by reducing angiogenesis and increasing blood vessel hyperpermeability. The encoded protein is a crucial component of the bone morphogenetic protein signaling pathway. The Smad proteins are subject to complex regulation by post-translational modifications. Mutations or deletions in this gene have been shown to result in pancreatic cancer, juvenile polyposis syndrome, and hereditary hemorrhagic telangiectasia syndrome. [provided by RefSeq, May 2022]
SMAD4 Gene-Disease associations (from GenCC):
  • juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P, PanelApp Australia
  • Myhre syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
  • generalized juvenile polyposis/juvenile polyposis coli
    Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
  • juvenile polyposis syndrome
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • familial thoracic aortic aneurysm and aortic dissection
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • hereditary hemorrhagic telangiectasia
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • pulmonary arterial hypertension
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMAD4NM_005359.6 linkc.47G>A p.Cys16Tyr missense_variant Exon 2 of 12 ENST00000342988.8 NP_005350.1 Q13485A0A024R274

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMAD4ENST00000342988.8 linkc.47G>A p.Cys16Tyr missense_variant Exon 2 of 12 5 NM_005359.6 ENSP00000341551.3 Q13485
ENSG00000267699ENST00000590722.2 linkn.*70G>A non_coding_transcript_exon_variant Exon 3 of 9 2 ENSP00000465737.1 E7EUB6
ENSG00000267699ENST00000590722.2 linkn.*70G>A 3_prime_UTR_variant Exon 3 of 9 2 ENSP00000465737.1 E7EUB6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Jun 18, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.C16Y variant (also known as c.47G>A), located in coding exon 1 of the SMAD4 gene, results from a G to A substitution at nucleotide position 47. The cysteine at codon 16 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Juvenile polyposis syndrome Uncertain:1
Jan 21, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 16 of the SMAD4 protein (p.Cys16Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant has not been reported in the literature in individuals with SMAD4-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.48
T;D;T;T;T;D;T;D
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.78
D
MetaRNN
Pathogenic
0.91
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.3
.;M;.;.;.;M;.;.
PhyloP100
10
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-9.0
.;D;.;.;.;D;.;.
REVEL
Pathogenic
0.89
Sift
Pathogenic
0.0
.;D;.;.;.;D;.;.
Sift4G
Uncertain
0.0030
D;D;D;D;D;D;D;D
Polyphen
1.0
.;D;.;.;.;D;.;.
Vest4
0.92, 0.92, 0.93
MutPred
0.52
Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);
MVP
0.98
MPC
4.1
ClinPred
1.0
D
GERP RS
5.6
PromoterAI
-0.013
Neutral
Varity_R
0.95
gMVP
0.94
Mutation Taster
=25/75
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1555684993; hg19: chr18-48573463; API