rs141538225

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000224784.10(ACTA2):​c.78C>T​(p.Asp26=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,613,930 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000042 ( 1 hom. )

Consequence

ACTA2
ENST00000224784.10 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.38
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BP6
Variant 10-88948853-G-A is Benign according to our data. Variant chr10-88948853-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 263386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-1.38 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000309 (47/152224) while in subpopulation AFR AF= 0.00104 (43/41538). AF 95% confidence interval is 0.000789. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 47 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ACTA2NM_001613.4 linkuse as main transcriptc.78C>T p.Asp26= synonymous_variant 2/9 ENST00000224784.10 NP_001604.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ACTA2ENST00000224784.10 linkuse as main transcriptc.78C>T p.Asp26= synonymous_variant 2/91 NM_001613.4 ENSP00000224784 P1

Frequencies

GnomAD3 genomes
AF:
0.000309
AC:
47
AN:
152106
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00104
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000151
AC:
38
AN:
251074
Hom.:
1
AF XY:
0.000155
AC XY:
21
AN XY:
135672
show subpopulations
Gnomad AFR exome
AF:
0.00135
Gnomad AMR exome
AF:
0.000318
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000424
AC:
62
AN:
1461706
Hom.:
1
Cov.:
30
AF XY:
0.0000371
AC XY:
27
AN XY:
727142
show subpopulations
Gnomad4 AFR exome
AF:
0.000747
Gnomad4 AMR exome
AF:
0.000313
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000309
AC:
47
AN:
152224
Hom.:
0
Cov.:
32
AF XY:
0.000349
AC XY:
26
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.00104
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000290
Hom.:
0
Bravo
AF:
0.000332

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:3
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthDec 05, 2018- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 11, 2023This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthDec 13, 2023- -
Aortic aneurysm, familial thoracic 6 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 09, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.75
CADD
Benign
2.3
DANN
Benign
0.83

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: rs141538225; hg19: chr10-90708610; COSMIC: COSV56515903; API