Genetic Variant ACTA2:c.991-142C>A (chr10-88935508-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001613.4(ACTA2):c.991-142C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 911,238 control chromosomes in the GnomAD database, including 8,312 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.097 ( 930 hom., cov: 32)

Exomes 𝑓: 0.11 ( 7382 hom. )

Consequence

ACTA2
NM_001613.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.725

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 10-88935508-G-T is Benign according to our data. Variant chr10-88935508-G-T is described in ClinVar as [Benign]. Clinvar id is 1229059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA2	NM_001613.4 link	c.991-142C>A		intron_variant	Intron 8 of 8	ENST00000224784.10	NP_001604.1	P62736D2JYH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000224784.10 link	c.991-142C>A		intron_variant	Intron 8 of 8	1	NM_001613.4	ENSP00000224784.6		P62736

Frequencies

GnomAD3 genomes

AF:

0.0968

AC:

14717

AN:

152094

Hom.:

928

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0770

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.119

Gnomad ASJ

AF:

0.128

Gnomad EAS

AF:

0.268

Gnomad SAS

AF:

0.343

Gnomad FIN

AF:

0.0532

Gnomad MID

AF:

0.191

Gnomad NFE

AF:

0.0779

Gnomad OTH

AF:

0.115

GnomAD4 exome

AF:

0.112

AC:

85359

AN:

759026

Hom.:

7382

Cov.:

AF XY:

0.122

AC XY:

48337

AN XY:

395126

show subpopulations

African (AFR)

AF:

0.0793

AC:

1594

AN:

20096

American (AMR)

AF:

0.115

AC:

4107

AN:

35722

Ashkenazi Jewish (ASJ)

AF:

0.134

AC:

2679

AN:

20000

East Asian (EAS)

AF:

0.250

AC:

8345

AN:

33332

South Asian (SAS)

AF:

0.331

AC:

22228

AN:

67242

European-Finnish (FIN)

AF:

0.0594

AC:

2156

AN:

36306

Middle Eastern (MID)

AF:

0.154

AC:

655

AN:

4266

European-Non Finnish (NFE)

AF:

0.0777

AC:

39248

AN:

505244

Other (OTH)

AF:

0.118

AC:

4347

AN:

36818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

3367

6733

10100

13466

16833

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0967

AC:

14726

AN:

152212

Hom.:

930

Cov.:

AF XY:

0.103

AC XY:

7646

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0771

AC:

3201

AN:

41542

American (AMR)

AF:

0.119

AC:

1826

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

443

AN:

3472

East Asian (EAS)

AF:

0.268

AC:

1383

AN:

5170

South Asian (SAS)

AF:

0.343

AC:

1656

AN:

4822

European-Finnish (FIN)

AF:

0.0532

AC:

564

AN:

10600

Middle Eastern (MID)

AF:

0.185

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0779

AC:

5300

AN:

68000

Other (OTH)

AF:

0.118

AC:

248

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

666

1331

1997

2662

3328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0853

Hom.:

101

Bravo

AF:

0.0956

Asia WGS

AF:

0.288

AC:

999

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.8

(source)

DANN

Benign

0.80

PhyloP100

-0.72

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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10-88935508-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over