rs1060500772

Positions:

• chr15-67190527-T-A
• chr15-67190527-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_005902.4(SMAD3):​c.1269T>A​(p.Ser423Arg) 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 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. S423G) 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: -0.755

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]

SMAD3 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain MH2 (size 193) in uniprot entity SMAD3_HUMAN there are 36 pathogenic changes around while only 0 benign (100%) 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 chr15-67190525-A-G is described in Lovd as [Likely_pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.1269T>A	p.Ser423Arg	missense_variant	9/9	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.1269T>A	p.Ser423Arg	missense_variant	9/9	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2016

This sequence change replaces serine with arginine at codon 423 of the SMAD3 protein (p.Ser423Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SMAD3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.78
MutPred		0.41		Gain of MoRF binding (P = 0.0026);.;.;.;
MVP		0.97
MPC		2.5
ClinPred		1.0	D
GERP RS		-8.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs1060500772; hg19: chr15-67482865;