rs794728028

Variant names:

• chr10-88939507-C-T
• rs794728028
• NM_001613.4:c.808G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PP2 PP3_Strong PP5 BS2

The NM_001613.4(ACTA2):​c.808G>A​(p.Gly270Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/25 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ACTA2 NM_001613.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4
• Conservation: PhyloP100: 7.91

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP2: Missense variant in the ACTA2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Trascript score misZ: 4.6117 (above the threshold of 3.09). GenCC associations: The gene is linked to familial thoracic aortic aneurysm and aortic dissection, connective tissue disorder, aortic aneurysm, familial thoracic 6, multisystemic smooth muscle dysfunction syndrome, Moyamoya disease 5.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 10-88939507-C-T is Pathogenic according to our data. Variant chr10-88939507-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199675.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=4, Pathogenic=1}. Variant chr10-88939507-C-T is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA2	NM_001613.4	c.808G>A	p.Gly270Arg	missense_variant, splice_region_variant	Exon 7 of 9	ENST00000224784.10	NP_001604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000224784.10	c.808G>A	p.Gly270Arg	missense_variant, splice_region_variant	Exon 7 of 9	1	NM_001613.4	ENSP00000224784.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250820 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135566

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460648 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726654

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:3

Aug 23, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with arginine at codon 270 of the ACTA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). However, this variant causes a G>A nucleotide substitution at the last nucleotide of exon 7 of the ACTA2 gene, and splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least four unrelated individuals affected with aortic dissection or aneurysm (PMID: 25759435, 26188975). This variant has been identified in 1/250820 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Apr 03, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G270R variant (also known as c.808G>A), located in coding exon 6 of the ACTA2 gene, results from a G to A substitution at nucleotide position 808. This change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the glycine at codon 270 to arginine, an amino acid with dissimilar properties. This alteration has been reported in two individuals with suspected familial thoracic aortic aneurysm (Regalado ES et al. Circ Cardiovasc Genet, 2015 Jun;8:457-64; Ziganshin BA et al. Ann. Thorac. Surg., 2015 Nov;100:1604-11). Another alteration affecting this amino acid (p.G270E, c.809G>A) has been identified in a single individual with thoracic aortic aneurysm and has been reported to co-segregate with disease (Bee KJ et al. Circ Cardiovasc Genet, 2012 Dec;5:621-9). Both the nucleotide and amino acid positions are highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, and is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Jan 25, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aortic aneurysm, familial thoracic 6 Pathogenic:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 270 of the ACTA2 protein (p.Gly270Arg). This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. This variant is present in population databases (rs794728028, gnomAD 0.0009%). This missense change has been observed in individuals with thoracic aortic aneurysm and dissection (PMID: 25759435, 26188975, 29543232). ClinVar contains an entry for this variant (Variation ID: 199675). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Oct 03, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACTA2 c.808G>A (p.Gly270Arg) variant has been reported in at least three individuals affected with aortic root aneurysm (Regalado ES et al., PMID: 25759435; Weerakkody R et al., PMID: 29543232; Ziganshin BA et al., PMID: 26188975). This variant is only observed on 1/250,820 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Another variant in the same codon, c.809G>A (p.Gly270Glu), has been reported in affected individuals and is considered pathogenic (Bee KJ et al., PMID: 23099432, ClinVar Variation ID: 199676). Computational predictors indicate that the variant is damaging, evidence that correlates with impact on ACTA2 function. This variant has been reported in the ClinVar database as a germline pathogenic variant by one submitter and a variant of uncertain significance by four submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic. -

not provided Uncertain:1

Aug 14, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The G270R variant in the ACTA2 gene has been reported previously in one individual with an aortic event at age 69 (Regalado et al., 2015). The G270R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G270R variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. As an alternate mechanism, multiple splicing algorithms predict that c.808 G>A (aka G270R) destroys the splice donor site for intron 7 which may cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of c.808 G>A in this individual is unknown. Other missense variants in the same (G270E) and nearby (G275A) residues have been reported in the Human Gene Mutation Database in association with thoracic aortic aneurysms (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret G270R as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.93
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.91		Loss of glycosylation at S267 (P = 0.0456);
MVP		0.97
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.84
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.46		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs794728028; hg19: chr10-90699264; COSMIC: COSV56515860; COSMIC: COSV56515860;