rs794728034

Variant names:

• chr10-88935336-CAG-C
• rs794728034
• NM_001613.4:c.1019_1020delCT

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001613.4(ACTA2):​c.1019_1020delCT​(p.Ser340CysfsTer26) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACTA2 NM_001613.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 10.0

Genes affected

ACTA2 (HGNC:130): (actin alpha 2, smooth muscle) This gene encodes one of six different actin proteins. Actins are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling. The encoded protein is a smooth muscle actin that is involved in vascular contractility and blood pressure homeostasis. Mutations in this gene cause a variety of vascular diseases, such as thoracic aortic disease, coronary artery disease, stroke, and Moyamoya disease, as well as multisystemic smooth muscle dysfunction syndrome. [provided by RefSeq, Sep 2017]

STAMBPL1 (HGNC:24105): (STAM binding protein like 1) Predicted to enable Lys63-specific deubiquitinase activity and thiol-dependent deubiquitinase. Predicted to be involved in protein K63-linked deubiquitination. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACTA2-AS1 (HGNC:45169): (ACTA2 antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.101 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA2	NM_001613.4	c.1019_1020delCT	p.Ser340CysfsTer26	frameshift_variant	Exon 9 of 9	ENST00000224784.10	NP_001604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000224784.10	c.1019_1020delCT	p.Ser340CysfsTer26	frameshift_variant	Exon 9 of 9	1	NM_001613.4	ENSP00000224784.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461656 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Jul 25, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 2 nucleotides in exon 9 of the ACTA2 gene, creating a frameshift and premature translation stop signal in the last exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. This variant has been reported in an individual affected with familial thoracic aortic aneurysm and dissection (PMID: 21937134) and in an individual affected with both thoracic aortic aneurysm and dissection and atrial septal defect (PMID: 36053285). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Multisystemic smooth muscle dysfunction syndrome Uncertain:1

Nov 06, 2022

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aortic aneurysm, familial thoracic 6 Uncertain:1

Nov 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser340Cysfs*26) in the ACTA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 38 amino acid(s) of the ACTA2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with clinical features of thoracic aortic aneurysm and dissection (PMID: 21937134; Invitae). ClinVar contains an entry for this variant (Variation ID: 199682). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

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: rs794728034; hg19: chr10-90695093;