rs1060500773

Variant names:

• chr15-67165277-GCCACA-G
• rs1060500773
• NM_005902.4:c.427_431delCACAC

Variant summary

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

The NM_005902.4(SMAD3):​c.427_431delCACAC​(p.His143ArgfsTer21) 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: 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 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 15-67165277-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 rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.427_431delCACAC	p.His143ArgfsTer21	frameshift_variant	Exon 3 of 9	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.427_431delCACAC	p.His143ArgfsTer21	frameshift_variant	Exon 3 of 9	1	NM_005902.4	ENSP00000332973.4

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

Nov 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMAD3-related conditions. ClinVar contains an entry for this variant (Variation ID: 405569). -

not provided Pathogenic:1

Dec 21, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

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;