rs1554841834

chr10-88947320-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_001613.4(ACTA2):c.196A>C(p.Ile66Leu) variant causes a missense change involving the alteration of a 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I66I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTA2 NM_001613.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001613.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ACTA2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTA2	NM_001613.4	c.196A>C	p.Ile66Leu	missense_variant	3/9	ENST00000224784.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTA2	ENST00000224784.10	c.196A>C	p.Ile66Leu	missense_variant	3/9	1	NM_001613.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aortic aneurysm, familial thoracic 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 02, 2017

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. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ACTA2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with leucine at codon 66 of the ACTA2 protein (p.Ile66Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;.;T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.1	N;N;N
REVEL	Pathogenic	0.73
Sift4G	Benign	0.12	T;.;.
Polyphen		0.0030	B;.;.
Vest4		0.60
MutPred		0.57		Gain of catalytic residue at I66 (P = 0.0174);Gain of catalytic residue at I66 (P = 0.0174);Gain of catalytic residue at I66 (P = 0.0174);
MVP		0.93
ClinPred		0.91	D
GERP RS		5.6
Varity_R		0.74
gMVP		0.92

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: rs1554841834; hg19: chr10-90707077;