chr10-88947378-C-A

Variant names:

• chr10-88947378-C-A
• rs878854466
• NM_001613.4:c.138G>T

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001613.4(ACTA2):​c.138G>T​(p.Met46Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M46V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACTA2 NM_001613.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.91
• 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: Pathogenic. The variant received 21 ACMG points.

• PS1: Transcript NM_001613.4 (ACTA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001613.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-88947380-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1421069.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant 10-88947378-C-A is Pathogenic according to our data. Variant chr10-88947378-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 664017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001613.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	NM_001613.4	MANE Select	c.138G>T	p.Met46Ile	missense	Exon 3 of 9	NP_001604.1
	ACTA2	NM_001141945.3		c.138G>T	p.Met46Ile	missense	Exon 3 of 9	NP_001135417.1
	ACTA2	NM_001320855.2		c.138G>T	p.Met46Ile	missense	Exon 3 of 9	NP_001307784.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	ENST00000224784.10	TSL:1 MANE Select	c.138G>T	p.Met46Ile	missense	Exon 3 of 9	ENSP00000224784.6
	ACTA2	ENST00000713598.1		c.138G>T	p.Met46Ile	missense	Exon 3 of 9	ENSP00000518894.1
	ACTA2	ENST00000415557.2	TSL:3	c.138G>T	p.Met46Ile	missense	Exon 3 of 9	ENSP00000396730.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Jun 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aortic aneurysm, familial thoracic 6 Pathogenic:1

Sep 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met46 amino acid residue in ACTA2. Other variant(s) that disrupt this residue have been observed in individuals with ACTA2-related conditions (PMID: 30975232; Invitae), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt ACTA2 protein function. ClinVar contains an entry for this variant (Variation ID: 664017). This missense change has been observed in individuals with clinical features of thoracic aortic aneurysms and dissections (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 46 of the ACTA2 protein (p.Met46Ile).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.84
Sift4G	Benign	0.11	T
Polyphen		0.098	B
Vest4		0.68
MutPred		0.83		Gain of catalytic residue at M46 (P = 0.059)
MVP		0.90
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.74
gMVP		0.90
Mutation Taster		=37/63	disease causing

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

Other links and lift over

dbSNP: rs878854466; hg19: chr10-90707135;