rs863223746

chr15-67187472-C-Achr15-67187472-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_005902.4(SMAD3):c.1117C>A(p.Arg373Ser) variant causes a missense change. 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. R373C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD3 NM_005902.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.99

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_005902.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-67187472-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213774.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=4, Pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, SMAD3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.1117C>A	p.Arg373Ser	missense_variant	8/9	ENST00000327367.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.1117C>A	p.Arg373Ser	missense_variant	8/9	1	NM_005902.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 26, 2018

This variant disrupts the p.Arg373 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 25944730, Invitae), which suggests that this may be a clinically significant amino acid residue. 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. 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 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 arginine with serine at codon 373 of the SMAD3 protein (p.Arg373Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.6	D;D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.014	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.90
MutPred		0.92		Loss of MoRF binding (P = 0.0463);.;.;.;
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.99

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

Other links and lift over

dbSNP: rs863223746; hg19: chr15-67479810;