18-47841853-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate

The NM_005901.6(SMAD2):​c.1378T>A​(p.Ser460Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

SMAD2
NM_005901.6 missense

Scores

2
5
12

Clinical Significance

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

Conservation

PhyloP100: 4.21
Variant links:
Genes affected
SMAD2 (HGNC:6768): (SMAD family member 2) The protein encoded by this gene belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein mediates the signal of the transforming growth factor (TGF)-beta, and thus regulates multiple cellular processes, such as cell proliferation, apoptosis, and differentiation. This protein is recruited to the TGF-beta receptors through its interaction with the SMAD anchor for receptor activation (SARA) protein. In response to TGF-beta signal, this protein is phosphorylated by the TGF-beta receptors. The phosphorylation induces the dissociation of this protein with SARA and the association with the family member SMAD4. The association with SMAD4 is important for the translocation of this protein into the nucleus, where it binds to target promoters and forms a transcription repressor complex with other cofactors. This protein can also be phosphorylated by activin type 1 receptor kinase, and mediates the signal from the activin. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, May 2012]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a domain MH2 (size 193) in uniprot entity SMAD2_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_005901.6
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMAD2. . Gene score misZ 3.6626 (greater than the threshold 3.09). Trascript score misZ 4.4705 (greater than threshold 3.09). GenCC has associacion of gene with Loeys-Dietz syndrome 6, congenital heart disease, familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome, congenital heart defects, multiple types, 8, with or without heterotaxy.
BP4
Computational evidence support a benign effect (MetaRNN=0.19383001).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMAD2NM_005901.6 linkuse as main transcriptc.1378T>A p.Ser460Thr missense_variant 11/11 ENST00000262160.11 NP_005892.1 Q15796-1Q53XR6
SMAD2NM_001003652.4 linkuse as main transcriptc.1378T>A p.Ser460Thr missense_variant 11/11 NP_001003652.1 Q15796-1Q53XR6
SMAD2NM_001135937.3 linkuse as main transcriptc.1288T>A p.Ser430Thr missense_variant 10/10 NP_001129409.1 B7Z5N5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMAD2ENST00000262160.11 linkuse as main transcriptc.1378T>A p.Ser460Thr missense_variant 11/111 NM_005901.6 ENSP00000262160.6 Q15796-1
SMAD2ENST00000402690.6 linkuse as main transcriptc.1378T>A p.Ser460Thr missense_variant 11/111 ENSP00000384449.1 Q15796-1
SMAD2ENST00000356825.8 linkuse as main transcriptc.1288T>A p.Ser430Thr missense_variant 10/101 ENSP00000349282.4 Q15796-2
SMAD2ENST00000586040.5 linkuse as main transcriptc.1288T>A p.Ser430Thr missense_variant 9/95 ENSP00000466193.1 Q15796-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 20, 2023The p.S460T variant (also known as c.1378T>A), located in coding exon 10 of the SMAD2 gene, results from a T to A substitution at nucleotide position 1378. The serine at codon 460 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 13, 2021Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
CADD
Benign
21
DANN
Benign
0.79
DEOGEN2
Uncertain
0.48
T;T;.;.
Eigen
Benign
-0.18
Eigen_PC
Benign
0.062
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.84
.;T;T;.
M_CAP
Benign
0.034
D
MetaRNN
Benign
0.19
T;T;T;T
MetaSVM
Uncertain
-0.056
T
MutationAssessor
Benign
0.88
L;L;.;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-0.97
N;N;N;.
REVEL
Uncertain
0.35
Sift
Benign
0.66
T;T;T;.
Sift4G
Benign
0.66
T;T;T;T
Polyphen
0.0010
B;B;B;B
Vest4
0.28
MutPred
0.14
Loss of disorder (P = 0.0718);Loss of disorder (P = 0.0718);.;.;
MVP
0.90
MPC
1.0
ClinPred
0.53
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.47
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-45368224; API