rs727502878

Positions:

• chr10-88939595-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001613.4(ACTA2):​c.720G>C​(p.Lys240Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA2 NM_001613.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 2.11

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-AS1 (HGNC:45169): (ACTA2 antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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). The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. GenCC has associacion of the 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, 0.878
• PP5: Variant 10-88939595-C-G is Pathogenic according to our data. Variant chr10-88939595-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162701.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA2	NM_001613.4	c.720G>C	p.Lys240Asn	missense_variant	7/9	ENST00000224784.10	NP_001604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000224784.10	c.720G>C	p.Lys240Asn	missense_variant	7/9	1	NM_001613.4	ENSP00000224784.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 20, 2017	The p.Lys240Asn variant in ACTA2 has been identified by our laboratory in 1 indi vidual with familial thoracic aortic aneurysms/dissections (TAAD) and segregated with disease in at least 5 affected relatives including 3 obligate carriers (Pr evention Genetics and LMM, unpublished data). It was absent from large populatio n studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are r equired to fully establish its clinical significance, the p.Lys240Asn variant is likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 20, 2020	- -

Aortic aneurysm, familial thoracic 6 Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 06, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 17, 2019	This sequence change replaces lysine with asparagine at codon 240 of the ACTA2 protein (p.Lys240Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with thoracic aortic aneurysm and dissection (Invitae). ClinVar contains an entry for this variant (Variation ID: 162701). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.73
Sift4G	Uncertain	0.017	D
Polyphen		0.76	P
Vest4		0.68
MutPred		0.63		Loss of ubiquitination at K240 (P = 0.0023);
MVP		0.95
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.94
gMVP		0.96

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: rs727502878; hg19: chr10-90699352;