10-88941407-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001613.4(ACTA2):c.455-17G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00842 in 1,613,720 control chromosomes in the GnomAD database, including 397 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (354 hom.)
• Consequence: ACTA2 NM_001613.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.325

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-88941407-C-T is Benign according to our data. Variant chr10-88941407-C-T is described in ClinVar as [Benign]. Clinvar id is 35644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-88941407-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTA2	NM_001613.4	c.455-17G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000224784.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTA2	ENST00000224784.10	c.455-17G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001613.4	P1

Frequencies

GnomAD3 genomes AF: 0.00836 AC: 1271 AN: 151998 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.0214

Gnomad FIN AF: 0.000568

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00503

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0146 AC: 3656 AN: 250896 Hom.: 163 AF XY: 0.0145 AC XY: 1970 AN XY: 135580

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.132

Gnomad SAS exome AF: 0.0138

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00500

Gnomad OTH exome AF: 0.00914

GnomAD4 exome AF: 0.00842 AC: 12305 AN: 1461606 Hom.: 354 Cov.: 31 AF XY: 0.00873 AC XY: 6348 AN XY: 727110

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.00390

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.0151

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.00473

Gnomad4 OTH exome AF: 0.0119

GnomAD4 genome AF: 0.00839 AC: 1276 AN: 152114 Hom.: 43 Cov.: 32 AF XY: 0.00923 AC XY: 686 AN XY: 74338

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00419

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.121

Gnomad4 SAS AF: 0.0216

Gnomad4 FIN AF: 0.000568

Gnomad4 NFE AF: 0.00503

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00363 Hom.: 2

Bravo AF: 0.00941

Asia WGS AF: 0.0750 AC: 260 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Familial aortopathy Benign:1

Benign, criteria provided, single submitter

curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Aortic aneurysm, familial thoracic 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.4
Dann	Benign	0.60

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

Other links and lift over

dbSNP: rs3816245; hg19: chr10-90701164; COSMIC: COSV56516719; COSMIC: COSV56516719;