10-88938205-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001613.4(ACTA2):​c.846C>T​(p.Asn282=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000409 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

ACTA2
NM_001613.4 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.30
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]
ACTA2-AS1 (HGNC:45169): (ACTA2 antisense RNA 1)
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 -18 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.26).
BP6
Variant 10-88938205-G-A is Benign according to our data. Variant chr10-88938205-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 536920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000854 (13/152260) while in subpopulation AMR AF= 0.000523 (8/15298). AF 95% confidence interval is 0.00026. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ACTA2NM_001613.4 linkuse as main transcriptc.846C>T p.Asn282= synonymous_variant 8/9 ENST00000224784.10 NP_001604.1
ACTA2-AS1NR_125373.1 linkuse as main transcriptn.1199-7G>A splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ACTA2ENST00000224784.10 linkuse as main transcriptc.846C>T p.Asn282= synonymous_variant 8/91 NM_001613.4 ENSP00000224784 P1
ACTA2-AS1ENST00000437930.4 linkuse as main transcriptn.1240-7G>A splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152142
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000524
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:
0.0000441
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000558
AC:
14
AN:
251092
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135686
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000318
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000265
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000363
AC:
53
AN:
1461760
Hom.:
0
Cov.:
31
AF XY:
0.0000289
AC XY:
21
AN XY:
727184
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000268
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000342
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152260
Hom.:
0
Cov.:
31
AF XY:
0.0000806
AC XY:
6
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000523
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000945

ClinVar

Significance: Likely benign
Submissions summary: Benign:5
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 HealthNov 18, 2018- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 27, 2020This 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 HealthFeb 05, 2024- -
ACTA2-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 31, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Aortic aneurysm, familial thoracic 6 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 25, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.26
CADD
Benign
13
DANN
Benign
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: rs375251378; hg19: chr10-90697962; API