Genetic Variant ACTA2:c.991-1091A>C (chr10-88936457-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001613.4(ACTA2):c.991-1091A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 151,960 control chromosomes in the GnomAD database, including 26,064 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.58 ( 26064 hom., cov: 31)

Consequence

ACTA2
NM_001613.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.217

Publications

1 publications found

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 links:

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]

STAMBPL1 links:

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

ACTA2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.99).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.876 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001613.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ACTA2	NM_001613.4	MANE Select	c.991-1091A>C	intron	N/A	NP_001604.1
ACTA2	NM_001141945.3		c.991-1091A>C	intron	N/A	NP_001135417.1
ACTA2	NM_001320855.2		c.991-1091A>C	intron	N/A	NP_001307784.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ACTA2	ENST00000224784.10	TSL:1 MANE Select	c.991-1091A>C	intron	N/A	ENSP00000224784.6
STAMBPL1	ENST00000371927.7	TSL:2	c.1254+14021T>G	intron	N/A	ENSP00000360995.3
ACTA2	ENST00000713598.1		c.1033-1091A>C	intron	N/A	ENSP00000518894.1

Frequencies

GnomAD3 genomes

AF:

0.576

AC:

87498

AN:

151842

Hom.:

26015

Cov.:

show subpopulations

Gnomad AFR

AF:

0.638

Gnomad AMI

AF:

0.468

Gnomad AMR

AF:

0.672

Gnomad ASJ

AF:

0.639

Gnomad EAS

AF:

0.897

Gnomad SAS

AF:

0.767

Gnomad FIN

AF:

0.421

Gnomad MID

AF:

0.636

Gnomad NFE

AF:

0.500

Gnomad OTH

AF:

0.602

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.576

AC:

87603

AN:

151960

Hom.:

26064

Cov.:

AF XY:

0.581

AC XY:

43122

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.639

AC:

26451

AN:

41410

American (AMR)

AF:

0.673

AC:

10277

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.639

AC:

2213

AN:

3464

East Asian (EAS)

AF:

0.898

AC:

4644

AN:

5174

South Asian (SAS)

AF:

0.769

AC:

3704

AN:

4816

European-Finnish (FIN)

AF:

0.421

AC:

4447

AN:

10554

Middle Eastern (MID)

AF:

0.622

AC:

183

AN:

294

European-Non Finnish (NFE)

AF:

0.500

AC:

33991

AN:

67956

Other (OTH)

AF:

0.601

AC:

1266

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1808

3616

5425

7233

9041

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

738

1476

2214

2952

3690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.536

Hom.:

2782

Bravo

AF:

0.595

Asia WGS

AF:

0.809

AC:

2812

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

2.2

(source)

DANN

Benign

0.72

PhyloP100

-0.22

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over