NM_001613.4:c.257A>G

Variant names:

• chr10-88947259-T-C
• rs1554841831
• NM_001613.4:c.257A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_001613.4(ACTA2):​c.257A>G​(p.Lys86Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K86N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACTA2 NM_001613.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a modified_residue N6-methyllysine (size 0) in uniprot entity ACTA_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• 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 multisystemic smooth muscle dysfunction syndrome, connective tissue disorder, familial thoracic aortic aneurysm and aortic dissection, Moyamoya disease 5, aortic aneurysm, familial thoracic 6.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA2	NM_001613.4	c.257A>G	p.Lys86Arg	missense_variant, splice_region_variant	Exon 3 of 9	ENST00000224784.10	NP_001604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000224784.10	c.257A>G	p.Lys86Arg	missense_variant, splice_region_variant	Exon 3 of 9	1	NM_001613.4	ENSP00000224784.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461530 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727050

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111776

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aortic aneurysm, familial thoracic 6 Uncertain:2

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 536919). This variant has not been reported in the literature in individuals affected with ACTA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 86 of the ACTA2 protein (p.Lys86Arg). -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Jul 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K86R variant (also known as c.257A>G), located in coding exon 2 of the ACTA2 gene, results from an A to G substitution at nucleotide position 257. The lysine at codon 86 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is conserved. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	1.7	L;.;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.6	N;N;N
REVEL	Pathogenic	0.85
Sift4G	Benign	0.11	T;.;.
Polyphen		0.041	B;.;.
Vest4		0.71
MutPred		0.72		Loss of methylation at K86 (P = 0.0015);Loss of methylation at K86 (P = 0.0015);Loss of methylation at K86 (P = 0.0015);
MVP		0.97
ClinPred		0.92	D
GERP RS		5.6
Varity_R		0.84
gMVP		0.82
Mutation Taster		=25/75	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1554841831; hg19: chr10-90707016;