18-47841853-A-T

Variant names:

• chr18-47841853-A-T
• NM_005901.6:c.1378T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.21

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]

ACMG classification

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 the SMAD2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 3.6626 (above the threshold of 3.09). Trascript score misZ: 4.4705 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
SMAD2	NM_005901.6	c.1378T>A	p.Ser460Thr	missense_variant	Exon 11 of 11	ENST00000262160.11	NP_005892.1
SMAD2	NM_001003652.4	c.1378T>A	p.Ser460Thr	missense_variant	Exon 11 of 11		NP_001003652.1
SMAD2	NM_001135937.3	c.1288T>A	p.Ser430Thr	missense_variant	Exon 10 of 10		NP_001129409.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD2	ENST00000262160.11	c.1378T>A	p.Ser460Thr	missense_variant	Exon 11 of 11	1	NM_005901.6	ENSP00000262160.6
SMAD2	ENST00000402690.6	c.1378T>A	p.Ser460Thr	missense_variant	Exon 11 of 11	1		ENSP00000384449.1
SMAD2	ENST00000356825.8	c.1288T>A	p.Ser430Thr	missense_variant	Exon 10 of 10	1		ENSP00000349282.4
SMAD2	ENST00000586040.5	c.1288T>A	p.Ser430Thr	missense_variant	Exon 9 of 9	5		ENSP00000466193.1

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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

Apr 13, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has 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;