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rs397515325

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP2PP3_ModeratePP5

The NM_001613.4(ACTA2):c.145A>G(p.Met49Val) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M49T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

ACTA2
NM_001613.4 missense

Scores

8
6
4

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.02
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr10-88947370-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 519576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant where missense usually causes diseases, ACTA2
PP3
MetaRNN computational evidence supports a deleterious effect, 0.922
PP5
Variant 10-88947371-T-C is Pathogenic according to our data. Variant chr10-88947371-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 65450.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ACTA2NM_001613.4 linkuse as main transcriptc.145A>G p.Met49Val missense_variant 3/9 ENST00000224784.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ACTA2ENST00000224784.10 linkuse as main transcriptc.145A>G p.Met49Val missense_variant 3/91 NM_001613.4 P1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Aortic aneurysm, familial thoracic 6 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 2011- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
Cadd
Uncertain
25
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.59
D;T;T
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.97
D;.;D
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.92
D;D;D
MetaSVM
Pathogenic
0.84
D
MutationAssessor
Benign
1.8
L;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-1.7
N;N;N
REVEL
Pathogenic
0.85
Sift4G
Benign
0.069
T;.;.
Polyphen
0.023
B;.;.
Vest4
0.91
MutPred
0.84
Loss of ubiquitination at K52 (P = 0.0665);Loss of ubiquitination at K52 (P = 0.0665);Loss of ubiquitination at K52 (P = 0.0665);
MVP
1.0
ClinPred
0.92
D
GERP RS
5.6
Varity_R
0.92
gMVP
0.90

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397515325; hg19: chr10-90707128; API