rs112901682

chr10-88948816-G-Achr10-88948816-G-Cchr10-88948816-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001613.4(ACTA2):c.115C>T(p.Arg39Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R39G) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ACTA2 NM_001613.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 4.62

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 Pathogenic. Variant got 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-88948816-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 199665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, ACTA2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 10-88948816-G-A is Pathogenic according to our data. Variant chr10-88948816-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-88948816-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTA2	NM_001613.4	c.115C>T	p.Arg39Cys	missense_variant	2/9	ENST00000224784.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTA2	ENST00000224784.10	c.115C>T	p.Arg39Cys	missense_variant	2/9	1	NM_001613.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74284

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 15, 2023	The ACTA2 c.115C>T; p.Arg39Cys variant (rs112901682) is reported in multiple individuals with thoracic aortic disorders and shown to segregate with disease in affected family members (Campens 2015, Hoffjan 2011, Kaw 2022, Li 2021, Overwater 2018). This variant is also reported in ClinVar (Variation ID: 65449). This variant is only found on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.853). Additionally, other variants at this codon (p.Arg39Gly, p.Arg39His) are reported in individuals with aortic aneurysm and dissection and are considered to be causative (Hoffjan 2011, Overwater 2018, Regalado 2015). Based on available information, the p.Arg39Cys variant is considered to be pathogenic. References: Campens L et al. Gene panel sequencing in heritable thoracic aortic disorders and related entities - results of comprehensive testing in a cohort of 264 patients. Orphanet J Rare Dis. 2015 Feb 3;10:9. PMID: 25644172. Hoffjan S et al. Three novel mutations in the ACTA2 gene in German patients with thoracic aortic aneurysms and dissections. Eur J Hum Genet. 2011 May;19(5):520-4. PMID: 21248741. Kaw A et al. Expanding ACTA2 genotypes with corresponding phenotypes overlapping with smooth muscle dysfunction syndrome. Am J Med Genet A. 2022 Aug;188(8):2389-2396. PMID: 35567597. Li J et al. Genetic testing and clinical relevance of patients with thoracic aortic aneurysm and dissection in northwestern China. Mol Genet Genomic Med. 2021 Oct;9(10):e1800. PMID: 34498425. Overwater E et al. Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders. Hum Mutat. 2018 Sep;39(9):1173-1192. PMID: 29907982. Regalado ES et al. Aortic Disease Presentation and Outcome Associated With ACTA2 Mutations. Circ Cardiovasc Genet. 2015 Jun;8(3):457-64. PMID: 25759435. -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21733706, 25644172, 25759435, 24243736, 21248741, 21937134, 30030203, 29907982, 31536524, 35567597, 36053285, 34498425) -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Jan 30, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 18, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 29, 2024	The p.R39C variant (also known as c.115C>T), located in coding exon 1 of the ACTA2 gene, results from a C to T substitution at nucleotide position 115. The arginine at codon 39 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with thoracic aortic aneurysm and dissection (TAAD), and co-segregation in affected relatives was reported in two unrelated families (Hoffjan S et al. Eur. J. Hum. Genet., 2011 May;19:520-4; Renard M et al. Int. J. Cardiol., 2013 May;165:314-21; Regalado ES et al. Am. J. Med. Genet. A, 2014 Jan;164A:106-12; Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192). Alternate amino acid substitutions at this position, p.R39H and p.R39G, have also been associated with TAAD and vascular disease findings (Guo DC et al. Am J Hum Genet. 2009;84(5):617-27; Regalado ES et al. Circ Cardiovasc Genet. 2015;8(3):457-64). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Aortic aneurysm, familial thoracic 6 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 18, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 39 of the ACTA2 protein (p.Arg39Cys). This variant is present in population databases (rs112901682, gnomAD 0.03%). This missense change has been observed in individuals with aortopathy (PMID: 21248741, 21733706, 21937134, 24243736, 25644172, 25759435). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65449). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACTA2 protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2011	- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Jul 18, 2022

ACMG categories: PS4,PM1,PM2,PP1,PP3,PP5,BP1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;D;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.9	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Pathogenic	0.85
Sift4G	Uncertain	0.058	T;.;.
Polyphen		0.040	B;.;.
Vest4		0.83
MutPred		0.86		Loss of methylation at R39 (P = 0.0262);Loss of methylation at R39 (P = 0.0262);Loss of methylation at R39 (P = 0.0262);
MVP		0.99
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.88
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112901682; hg19: chr10-90708573; COSMIC: COSV56518131;