rs397516683

Positions:

• chr10-88941820-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_001613.4(ACTA2):​c.419C>T​(p.Ala140Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ACTA2 NM_001613.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 9.94

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]

ACTA2 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.952
• PP5: Variant 10-88941820-G-A is Pathogenic according to our data. Variant chr10-88941820-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44217.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}. Variant chr10-88941820-G-A is described in Lovd as [Likely_pathogenic]. Variant chr10-88941820-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA2	NM_001613.4	c.419C>T	p.Ala140Val	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.419C>T	p.Ala140Val	missense_variant	5/9	1	NM_001613.4	ENSP00000224784.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460782 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726574

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Blueprint Genetics	Aug 22, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 20, 2022	The p.A140V variant (also known as c.419C>T), located in coding exon 4 of the ACTA2 gene, results from a C to T substitution at nucleotide position 419. The alanine at codon 140 is replaced by valine, an amino acid with similar properties. This alteration has been reported in individuals with thoracic aortic aneurysms and dissections (TAAD) and has demonstrated co-segregation with disease (Ambry internal data; GeneDx pers. comm.; Lerner-Ellis JP et al. Mol. Genet. Metab., 2014 Jun;112:171-6). This variant has also been detected in an individual with aortic dissections and in two of her family members, one with abdominal aortic rupture and one with abdominal aortic aneurysm (Overwater E et al. Hum Mutat, 2018 09;39:1173-1192). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Aortic aneurysm, familial thoracic 6 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 140 of the ACTA2 protein (p.Ala140Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of thoracic aortic aneurysm and dissection (TAAD) and/or thoracic aortic aneurysm and dissection (PMID: 24793577, 29907982; Invitae). ClinVar contains an entry for this variant (Variation ID: 44217). 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 expected to disrupt ACTA2 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 03, 2019

Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: The p.Ala140Val variant in ACTA2 is absent from gnomAD with adequate coverage. Computational predictors predict that the variant is damaging. The residue is entirely conserved and no species harbor the variant amino acid. It has been reported as pathogenic (2013) and Uncertain significance (2014) by two high-volume clinical labs. The variant has been reported in 1 LMM patient with TAAD (Lerner-Ellis 2014) and 1 additional TAAD patient (Overwater 2018). Both had family histories. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2022

Has been reported as a variant of uncertain significance in a patient with TAAD in published literature (Lerner-Ellis, et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 44217; ClinVar); This variant is associated with the following publications: (PMID: 24793577, 29907982) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Pathogenic	0.91
Sift4G	Uncertain	0.026	D;.;.
Polyphen		0.97	D;.;.
Vest4		0.85
MutPred		0.80		Loss of phosphorylation at Y135 (P = 0.3829);Loss of phosphorylation at Y135 (P = 0.3829);Loss of phosphorylation at Y135 (P = 0.3829);
MVP		0.94
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397516683; hg19: chr10-90701577;