rs780995229

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_005902.4(SMAD3):​c.72C>G​(p.Asn24Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SMAD3
NM_005902.4 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.51
Variant links:
Genes affected
SMAD3 (HGNC:6769): (SMAD family member 3) The SMAD family of proteins are a group of intracellular signal transducer proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. The SMAD3 protein functions in the transforming growth factor-beta signaling pathway, and transmits signals from the cell surface to the nucleus, regulating gene activity and cell proliferation. This protein forms a complex with other SMAD proteins and binds DNA, functioning both as a transcription factor and tumor suppressor. Mutations in this gene are associated with aneurysms-osteoarthritis syndrome and Loeys-Dietz Syndrome 3. [provided by RefSeq, May 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMAD3. . Gene score misZ 3.4782 (greater than the threshold 3.09). Trascript score misZ 4.3526 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, aneurysm-osteoarthritis syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.31460842).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMAD3NM_005902.4 linkuse as main transcriptc.72C>G p.Asn24Lys missense_variant 1/9 ENST00000327367.9 NP_005893.1 P84022-1A0A024R5Z3Q9P0T0
SMAD3NM_001407011.1 linkuse as main transcriptc.72C>G p.Asn24Lys missense_variant 1/10 NP_001393940.1
SMAD3NM_001407012.1 linkuse as main transcriptc.72C>G p.Asn24Lys missense_variant 1/8 NP_001393941.1
SMAD3NM_001407013.1 linkuse as main transcriptc.72C>G p.Asn24Lys missense_variant 1/8 NP_001393942.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMAD3ENST00000327367.9 linkuse as main transcriptc.72C>G p.Asn24Lys missense_variant 1/91 NM_005902.4 ENSP00000332973.4 P84022-1
SMAD3ENST00000560424.2 linkuse as main transcriptc.72C>G p.Asn24Lys missense_variant 1/103 ENSP00000455540.2 H3BQ00
SMAD3ENST00000559460.6 linkuse as main transcriptc.-110+2282C>G intron_variant 4 ENSP00000453082.2 H0YL71

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 14, 2018In 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. 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: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SMAD3-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with lysine at codon 24 of the SMAD3 protein (p.Asn24Lys). The asparagine residue is moderately conserved and there is a moderate physicochemical difference between asparagine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Benign
-0.071
T
BayesDel_noAF
Benign
-0.34
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
D
Eigen
Benign
-0.039
Eigen_PC
Benign
0.0064
FATHMM_MKL
Benign
0.75
D
LIST_S2
Benign
0.84
T
M_CAP
Benign
0.060
D
MetaRNN
Benign
0.31
T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
2.0
M
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-2.0
N
REVEL
Benign
0.17
Sift
Benign
0.062
T
Sift4G
Uncertain
0.038
D
Polyphen
0.88
P
Vest4
0.41
MutPred
0.34
Loss of loop (P = 0.0022);
MVP
0.84
MPC
1.6
ClinPred
0.79
D
GERP RS
1.6
Varity_R
0.34
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs780995229; hg19: chr15-67358564; API