rs794728025
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001613.4(ACTA2):c.446G>T(p.Arg149Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R149C) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
ACTA2
NM_001613.4 missense
NM_001613.4 missense
Scores
11
5
2
Clinical Significance
Conservation
PhyloP100: 5.96
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr10-88941794-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
?
Missense variant where missense usually causes diseases, ACTA2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.967
PP5
?
Variant 10-88941793-C-A is Pathogenic according to our data. Variant chr10-88941793-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 199671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTA2 | NM_001613.4 | c.446G>T | p.Arg149Leu | missense_variant | 5/9 | ENST00000224784.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTA2 | ENST00000224784.10 | c.446G>T | p.Arg149Leu | missense_variant | 5/9 | 1 | NM_001613.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 15, 2016 | p.Arg149Leu (CGC>CTC): c.446 G>T in exon 5 of the ACTA2 gene (NM_001613.2)While the R149L mutation in the ACTA2 gene has not been reported to our knowledge, a mutation affecting this same residue, R149C, has been reported in association with TAAD (Morisaki H et al., 2009; Guo DC et al., 2009). Additionally, mutations in nearby residues (Y145C, V154A) have been reported in association with TAAD, further supporting the functional importance of this residue and this region of the protein. R149L results in a non-conservative amino acid substitution of Laucine at a position that is highly conserved across species. In silico analysis predicts R149L is damaging to the protein structure/function. Furthermore, R149L was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, R149L in the ACTA2 gene is interpreted as a likely disease-causing mutation. The variant is found in TAAD panel(s). - |
Aortic aneurysm, familial thoracic 6 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 19, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg149 amino acid residue in ACTA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19409525, 21212136, 21248741, 24020716, 25644172). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACTA2 protein function. ClinVar contains an entry for this variant (Variation ID: 199671). This missense change has been observed in individual(s) with clinical features of ACTA2-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 149 of the ACTA2 protein (p.Arg149Leu). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift4G
Uncertain
T;.;.
Polyphen
P;.;.
Vest4
MutPred
Loss of methylation at R149 (P = 0.0106);Loss of methylation at R149 (P = 0.0106);Loss of methylation at R149 (P = 0.0106);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
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