rs878854465
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4
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
NM_001613.4 stop_lost
Scores
3
4
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Stoplost variant in NM_001613.4 Downstream stopcodon found after 47 codons.
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
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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 | - - |
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 - |
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. - |
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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;N;N
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at