chr18-51065519-A-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5
The NM_005359.6(SMAD4):c.1052A>T(p.Asp351Val) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
SMAD4
NM_005359.6 missense
NM_005359.6 missense
Scores
17
1
1
Clinical Significance
Conservation
PhyloP100: 9.14
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
In a domain MH2 (size 229) in uniprot entity SMAD4_HUMAN there are 40 pathogenic changes around while only 2 benign (95%) in NM_005359.6
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMAD4. . Gene score misZ 4.1308 (greater than the threshold 3.09). Trascript score misZ 4.9346 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, generalized juvenile polyposis/juvenile polyposis coli, hereditary hemorrhagic telangiectasia, Myhre syndrome, pulmonary arterial hypertension, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, juvenile polyposis syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 18-51065519-A-T is Pathogenic according to our data. Variant chr18-51065519-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 405499.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD4 | NM_005359.6 | c.1052A>T | p.Asp351Val | missense_variant | 9/12 | ENST00000342988.8 | NP_005350.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 27, 2020 | The p.D351V pathogenic mutation (also known as c.1052A>T), located in coding exon 8 of the SMAD4 gene, results from an A to T substitution at nucleotide position 1052. The aspartic acid at codon 351 is replaced by valine, an amino acid with highly dissimilar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with Juvenile Polyposis syndrome (JPS) (Ambry internal data). This variant has also been observed in individuals who have a personal or family history that is consistent with JPS (Ambry internal data). The same amino acid change has been reported in an individual with overlapping features of JPS and hereditary hemorrhagic telangiectasia (HTT) (Bishop JC et al. J Pediatr Genet, 2018 Jun;7:78-82). A different alteration in the same codon (p.D351H) has been observed in an individual with HTT (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Juvenile polyposis syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 22, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 351 of the SMAD4 protein (p.Asp351Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia and/or juvenile polyposis syndrome (PMID: 29707409; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 405499). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMAD4 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 28, 2018 | Variant summary: SMAD4 c.1052A>T (p.Asp351Val) results in a non-conservative amino acid change located in the dwarfin-type domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 121412 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1052A>T has been reported in the literature in an individual with colorectal cancer (Adua 2017) and Juvenile Polyposis (Bishop 2017), however neither report provides strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
SMAD4-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 09, 2024 | The SMAD4 c.1052A>T variant is predicted to result in the amino acid substitution p.Asp351Val. This variant was reported in an individual with juvenile idiopathic arthritis with combined JP-HHT syndrome (Bishop et al. 2018. PubMed ID: 29707409) and in a tumor sample from an individual with colorectal cancer (Adua et al. 2017. PubMed ID: 28685087). This variant has not been reported in a large population database, indicating this variant is rare. It has conflicting interpretations of uncertain and pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/405499/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;.
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;.
Vest4
MutPred
Loss of phosphorylation at Y353 (P = 0.0814);Loss of phosphorylation at Y353 (P = 0.0814);.;
MVP
MPC
3.5
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at