rs1060500773

chr15-67165277-GCCACA-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_005902.4(SMAD3):c.427_431del(p.His143ArgfsTer21) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMAD3 NM_005902.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.15

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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-67165277-GCCACA-G is Pathogenic according to our data. Variant chr15-67165277-GCCACA-G is described in ClinVar as [Pathogenic]. Clinvar id is 405569.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.427_431del	p.His143ArgfsTer21	frameshift_variant	3/9	ENST00000327367.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.427_431del	p.His143ArgfsTer21	frameshift_variant	3/9	1	NM_005902.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2022

This variant has not been reported in the literature in individuals affected with SMAD3-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 405569). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His143Argfs*21) 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). -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Dec 21, 2016

p.His143Argfs*21 (c.427_431delCACAC) in the SMAD3 gene (NM_005902.3) The lab classifies this variant as pathogenic. Given that loss of function is a known mechanism for disease in SMAD3 we consider this variant is disease causing and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been reported in other patients before. However, all eight loss-of-function variants in SMAD3 have been reported as pathogenic or likely pathogenic in clinvar and loss-of function has been published as a known mechanism for disease (PMID: 21778426, 24804794). In addition, this variant has also been identified in six other other family members, most of whom carry the diagnosis of Loeys-Dietz syndrome or have had vascular hemorrhages in the brain or thoracic aortic dilatation and dissection. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060500773; hg19: chr15-67457615;