rs863223754

Variant names:

• chr15-67184843-A-AC
• rs863223754
• NM_005902.4:c.990dupC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005902.4(SMAD3):​c.990dupC​(p.Val331ArgfsTer31) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD3 NM_005902.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.72

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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-67184843-A-AC is Pathogenic according to our data. Variant chr15-67184843-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 213787.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.990dupC	p.Val331ArgfsTer31	frameshift_variant	Exon 7 of 9	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.990dupC	p.Val331ArgfsTer31	frameshift_variant	Exon 7 of 9	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Dec 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with SMAD3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val331Argfs*31) in the SMAD3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMAD3 are known to be pathogenic (PMID: 21778426, 24804794). ClinVar contains an entry for this variant (Variation ID: 213787). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jul 13, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Members of this family have been tested at Invitae and GeneDx. Given that loss-of-function is a known mechanism for disease in SMAD3, which is associated with Loeys-Dietz syndrome and TAAD, we consider this variant to be disease causing and believe it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This specific variant has not been reported in the literature in association with disease as of 7/13/2017. However, it has segregated with thoracic aortic dilatation and dissection across at least 5 meioses in the family seen at our center. This sequence change inserts 1 nucleotide in exon 7 of the SMAD3 mRNA (c.990dupC), causing a frameshift at codon 331. This creates a premature translational stop signal (p.Val331Argfs*31) and is expected to result in an absent or disrupted protein product. It is absent from the 140,000 individuals in the gnomAD database. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs863223754; hg19: chr15-67477181;