10-88938111-G-A

Position:

• chr10-88938111-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001613.4(ACTA2):​c.940C>T​(p.Arg314*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,754 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACTA2 NM_001613.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.15

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.171 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-88938111-G-A is Pathogenic according to our data. Variant chr10-88938111-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 263926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA2	NM_001613.4	c.940C>T	p.Arg314*	stop_gained	8/9	ENST00000224784.10	NP_001604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000224784.10	c.940C>T	p.Arg314*	stop_gained	8/9	1	NM_001613.4	ENSP00000224784.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461754 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727182

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aortic aneurysm, familial thoracic 6 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	May 03, 2024	PVS1, PM2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 08, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 263926). This premature translational stop signal has been observed in individuals with clinical features of thoracic aortic aneurysms and dissections (PMID: 21937134). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg314*) in the ACTA2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ACTA2 cause disease. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with familial thoracic aortic aneurysm 6 (MIM#611788), moyamoya disease 5 (MIM#614042) and multisystemic smooth muscle dysfunction syndrome (MIM#613834) (PMIDs: 27551047, 28652363). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is predicted to truncate the annotated actin domain (DECIPHER). (I) 0710 - Other premature termination variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Despite being reported as VUS, p.(Ser340Cysfs*26), p.(Val341Cysfs*26) and p.(Gln356*) have been reported in individuals with aortic aneurysm/dissection, vertebral artery dissection and aortic root dilatation, respectively (ClinVar, personal communication). p.(Ser340Cysfs*26) has also been reported in the literature in affected individuals (PMIDs: 21937134, 36053285). p.(Trp342Ter) has been reported in an individual with Marfan syndrome, who also also has a VUS in the MYH11 gene (ClinVar, personal communication). (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple affected members of a family with thoracic aortic aneurysm / dissection (PMID: 21937134). It has also been reported as pathogenic by a clinical testing laboratory in one individual with aortic aneurysm and dissection, and one with familial hypercholesterolaemia, tetralogy of fallot and early repolarisation on EKG (ClinVar, personal communication). In addition, this variant has been reported as a VUS by another clinical testing laboratory, but without phenotypic information available (ClinVar, personal communication). (SP) 0902 - This variant has moderate evidence for segregation with disease. In the published literature, this variant has been reported in four individuals with thoracic aortic aneurysm / dissection from a multi-generational family and absent in three unaffected family members (PMID: 21937134). (SP) 1010 - Functional evidence for this variant is inconclusive. Immunohistochemistry study of the aortic tissue of an individual with this variant showed marked fragmentation of the elastic fibers and a defective fibronectin assembly in the tunica media (PMID: 21937134). The morphology of smooth muscle cells was also altered in that individual’s aortic tissue compared to the control tissue. TGFbeta signaling alteration was investigated; however, no increase in connective tissue growth factor or pSmad2 staining were seen in the individual’s aortic tissue. (I) 1207 - Parental origin of the variant is unresolved. Subsequent analysis has shown that this variant is not maternally inherited (LABID); however, a sample from this individual's father has not been tested. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2020

The p.R314* pathogenic mutation (also known as c.940C>T) located in coding exon 7 of the ACTA2 gene, results from a C to T substitution at nucleotide position 940. This changes the amino acid from an arginine to a stop codon within coding exon 7. In one study, this mutation was identified in multiple family members with aortic dilation or related features (Renard et al. Int J Cardiol. 2013;165(2):314-21). In addition to the clinical data presented in the literature, premature stop codons are typically deleterious in nature. Loss of function of ACTA2 has not been clearly established as a mechanism of disease, but this stop codon occurs at the 3' terminus of ACTA2 and is not expected to trigger nonsense-mediated mRNA decay. This alteration is predicted to remove the last 64 amino acids of the protein, and although the exact functional impact of these removed amino acids is unknown at this time, a downstream frameshift alteration (c.1019_1020delCT) has also been reported to segregate with ACTA2-related thoracic aortic aneurysm and dissection (Renard et al. Int J Cardiol. 2013;165(2):314-21). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.92	D
Vest4		0.97
GERP RS		4.2

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: rs886038978; hg19: chr10-90697868; COSMIC: COSV56516891; COSMIC: COSV56516891;