rs794728025

Positions:

• chr10-88941793-C-A
• chr10-88941793-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_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 Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA2 NM_001613.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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]

ACMG classification

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 Lovd as [Likely_pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTA2. . Trascript score misZ 4.6117 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, connective tissue disorder, aortic aneurysm, familial thoracic 6, multisystemic smooth muscle dysfunction syndrome, Moyamoya disease 5.
• 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	Protein	UniProt
ACTA2	NM_001613.4	c.446G>T	p.Arg149Leu	missense_variant	5/9	ENST00000224784.10	NP_001604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000224784.10	c.446G>T	p.Arg149Leu	missense_variant	5/9	1	NM_001613.4	ENSP00000224784	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

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

Labcorp Genetics (formerly Invitae), Labcorp

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D;D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T;.;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Pathogenic	0.92
Sift4G	Uncertain	0.051	T;.;.
Polyphen		0.77	P;.;.
Vest4		0.94
MutPred		0.88		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		0.98
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.99

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: rs794728025; hg19: chr10-90701550;