rs794728025

Variant names:

• chr10-88941793-C-A
• rs794728025
• NM_001613.4:c.446G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 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. R149H) has been classified as Uncertain significance.

• 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
• Publications: 4 publications found

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

Our verdict: Pathogenic. The variant received 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 VariationId is 18276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the ACTA2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Trascript score misZ: 4.6117 (above the threshold of 3.09). GenCC associations: The gene is linked to multisystemic smooth muscle dysfunction syndrome, connective tissue disorder, familial thoracic aortic aneurysm and aortic dissection, Moyamoya disease 5, aortic aneurysm, familial thoracic 6.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 199671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA2	NM_001613.4	c.446G>T	p.Arg149Leu	missense_variant	Exon 5 of 9	ENST00000224784.10	NP_001604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000224784.10	c.446G>T	p.Arg149Leu	missense_variant	Exon 5 of 9	1	NM_001613.4	ENSP00000224784.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Dec 15, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 199671). 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. 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. -

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;.;.
PhyloP100		6.0
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
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs794728025; hg19: chr10-90701550;