rs714887

Positions:

• chr10-88941888-A-G

Variant summary

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

The ENST00000224784.10(ACTA2):​c.370-19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0874 in 1,601,224 control chromosomes in the GnomAD database, including 8,887 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (765 hom., cov: 32)
  • Exomes 𝑓: 0.087 (8122 hom.)
• Consequence: ACTA2 ENST00000224784.10 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.729

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=-0.79).
• BP6: Variant 10-88941888-A-G is Benign according to our data. Variant chr10-88941888-A-G is described in ClinVar as [Benign]. Clinvar id is 136279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-88941888-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA2	NM_001613.4	c.370-19T>C		intron_variant		ENST00000224784.10	NP_001604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000224784.10	c.370-19T>C		intron_variant		1	NM_001613.4	ENSP00000224784	P1

Frequencies

GnomAD3 genomes AF: 0.0887 AC: 13497 AN: 152096 Hom.: 762 Cov.: 32

Gnomad AFR AF: 0.0767

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.0455

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0681

Gnomad OTH AF: 0.110

GnomAD3 exomes AF: 0.120 AC: 27865 AN: 231922 Hom.: 2434 AF XY: 0.127 AC XY: 15802 AN XY: 124906

Gnomad AFR exome AF: 0.0786

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.278

Gnomad SAS exome AF: 0.281

Gnomad FIN exome AF: 0.0529

Gnomad NFE exome AF: 0.0692

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.0872 AC: 126402 AN: 1449010 Hom.: 8122 Cov.: 31 AF XY: 0.0926 AC XY: 66633 AN XY: 719880

Gnomad4 AFR exome AF: 0.0769

Gnomad4 AMR exome AF: 0.114

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.255

Gnomad4 SAS exome AF: 0.272

Gnomad4 FIN exome AF: 0.0532

Gnomad4 NFE exome AF: 0.0654

Gnomad4 OTH exome AF: 0.107

GnomAD4 genome AF: 0.0887 AC: 13505 AN: 152214 Hom.: 765 Cov.: 32 AF XY: 0.0940 AC XY: 6997 AN XY: 74424

Gnomad4 AFR AF: 0.0768

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.267

Gnomad4 SAS AF: 0.281

Gnomad4 FIN AF: 0.0455

Gnomad4 NFE AF: 0.0681

Gnomad4 OTH AF: 0.113

Alfa AF: 0.0821 Hom.: 123

Bravo AF: 0.0891

Asia WGS AF: 0.273 AC: 949 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

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, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Aortic aneurysm, familial thoracic 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Thoracic aortic aneurysm Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	12
DANN	Benign	0.84

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: rs714887; hg19: chr10-90701645; COSMIC: COSV56517790; COSMIC: COSV56517790;