rs121434528

Positions:

chr10-88939543-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_001613.4(ACTA2):c.772C>T(p.Arg258Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ACTA2
NM_001613.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 10.0

Variant links:

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]

ACTA2 links:

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

ACTA2-AS1 links:

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]

STAMBPL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTA2. . Trascript score misZ 4.6117 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, connective tissue disorder, aortic aneurysm, familial thoracic 6, multisystemic smooth muscle dysfunction syndrome, Moyamoya disease 5.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 10-88939543-G-A is Pathogenic according to our data. Variant chr10-88939543-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18278.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 linkuse as main transcript	c.772C>T	p.Arg258Cys	missense_variant	7/9	ENST00000224784.10	NP_001604.1
ACTA2-AS1	NR_125373.1 linkuse as main transcript	n.1612G>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000224784.10 linkuse as main transcript	c.772C>T	p.Arg258Cys	missense_variant	7/9	1	NM_001613.4	ENSP00000224784	P1
ACTA2-AS1	ENST00000437930.4 linkuse as main transcript	n.1653G>A		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461652

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727132

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

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:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aortic aneurysm, familial thoracic 6

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 258 of the ACTA2 protein (p.Arg258Cys). This variant is present in population databases (rs121434528, gnomAD 0.007%). This missense change has been observed in individual(s) with nonsyndromic heritable thoracic aortic disorder and thoracic aortic aneurysms and patent ductus arteriosus (PMID: 17994018, 19409525, 25644172). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18278). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACTA2 function (PMID: 26153420). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 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) (PMID: 27551047, 28652363). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Actin domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in at least 10 unrelated individuals with thoracic aortic disorders and has been classified as pathogenic (ClinVar, PMID:33513575, PMID:19409525, PMID:25644172, PMID:36053285). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jun 06, 2023	This sequence change in ACTA2 is predicted to replace arginine with cysteine at codon 258, p.(Arg258Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the SM alpha-actin SD4 domain (PMID: 19409525). There is a large physicochemical difference between arginine and cysteine. ACTA2, in which the variant was identified, is a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (gnomAD v2.1). This variant is present in a single individual from the European (non-Finnish) population in the population database gnomAD v2.1 (1/68,040 alleles), which is consistent with ACTA2-related disease. This variant has been reported in multiple probands with thoracic aortic aneurysm and aortic dissection (TAAD) with/without premature stroke, and segregates with disease in multiple families (PMID: 19409525, 25644172, 25759435, 37042257). The variant has also been identified as a de novo occurrence with confirmed parental relationships in one family with cerebral arteriopathy and mild TAAD and as a de novo occurrence with unconfirmed parental relationships in one individual with TAAD (PMID: 19409525, 33513575). This variant alters protein function in a dominant negative manner in both in vitro functional assays and patient fibroblasts (PMID: 26153420, 28652363). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.932). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4_Moderate, PS2_Moderate/PM6, PP1_Moderate, PP3_Moderate, PS3_Supporting, PM2_Supporting, PP2, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 04, 2020	The p.R258C pathogenic mutation (also known as c.772C>T), located in coding exon 6 of the ACTA2 gene, results from a C to T substitution at nucleotide position 772. The arginine at codon 258 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was found to segregate with disease in two unrelated families with familial thoracic aortic aneurysms and dissections (TAAD) and premature ischemic strokes (Guo DC et al. Am J Hum Genet. 2009;84(5):617-27). This variant was also reported as de novo in one family with TAAD (Guo et al 2009). In addition, this variant very likely resulted from a de novo event in one family tested in our laboratory. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2024	Reported in association with premature stroke, PDA and TAAD in multiple unrelated probands and families (PMID: 25644172, 19409525, 25759435); Published functional studies demonstrate a damaging effect as this variant disrupts actin dynamics and leads to contractile dysfunction (PMID: 26153420, 28652363); 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: 17994018, 33513575, 26934405, 27879251, 28652363, 30341550, 30300893, 28848449, 25759435, 36053285, 34498425, 35567597, 37587538, 32814715, 33990081, 34546411, 34600884, 30880160, 36194209, 32464348, 32997990, 33776470, 34062765, 25644172, 26153420, PetrovI2022[Article], 19409525) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 17, 2017	- -

Moyamoya disease 5

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.4

REVEL

Pathogenic

0.93

Sift4G

Uncertain

0.021

Polyphen

1.0

Vest4

0.94

MutPred

0.92

Loss of catalytic residue at R258 (P = 0.039);

MVP

0.97

ClinPred

1.0

GERP RS

6.1

Varity_R

0.77

gMVP

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over