10-88935225-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001613.4(ACTA2):c.1132T>C(p.Ter378GlnextTer14) variant causes a stop lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. *378*) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA2 NM_001613.4 stop_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 9.24

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]

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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.0192286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTA2	NM_001613.4	c.1132T>C	p.Ter378GlnextTer14	stop_lost	9/9	ENST00000224784.10
ACTA2-AS1	NR_125373.1	n.850A>G		non_coding_transcript_exon_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTA2	ENST00000224784.10	c.1132T>C	p.Ter378GlnextTer14	stop_lost	9/9	1	NM_001613.4	P1
ACTA2-AS1	ENST00000437930.4	n.891A>G		non_coding_transcript_exon_variant	3/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 20, 2023	The c.1132T>C variant (also known as p.*378Qext*14), located in coding exon 8 of the ACTA2 gene, results from a T to C substitution at nucleotide position 1132. This alteration disrupts the stop codon of the ACTA2 gene and is predicted to preserve the native sequence while resulting in the elongation of the protein by 14 amino acids. The exact functional effect of the additional amino acids is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 14, 2019	- -

ACTA2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 27, 2022

The ACTA2 c.1132T>C variant is predicted to result in extension of the open reading frame (p.*378Glnext*14). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 18, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Normal stop codon changed to a Gln codon, leading to the addition of 14 amino acids at the C-terminus; Has not been previously published as pathogenic or benign to our knowledge -

Aortic aneurysm, familial thoracic 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2019

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. Experimental studies have not been published for this variant and the effect of this extension on protein function is unknown. This variant has been found in two related individuals affected with aortic root dilatation and dissection (Invitae). ClinVar contains an entry for this variant (Variation ID: 239035). This variant is not present in population databases (ExAC no frequency). This sequence change disrupts the translational stop signal of the ACTA2 mRNA. It is expected to extend the length of the ACTA2 protein by 13 additional amino acid residues. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	20
Dann	Benign	0.86
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;N;N
Vest4		0.29
GERP RS		5.6

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: rs878854465; hg19: chr10-90694982;