rs112602953

Variant names:

• chr10-88943813-C-T
• rs112602953
• NM_001613.4:c.353G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-88943813-C-T
• chr10-88943813-C-A
• chr10-88943813-C-G

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001613.4(ACTA2):​c.353G>A​(p.Arg118Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000287173: Experimental studies have shown that this missense change affects ACTA2 function (PMID:21288906).; SCV002557626: "This variant has strong functional evidence supporting abnormal protein function. Functional study using smooth muscle cells suggested that variant perturbs ACTA2 filament assembly or stability (PMID:17994018);"; SCV000710874: Studies on cultured smooth muscle cells (SMCs) derived from a heterozygous carrier of this variant suggest that this variant perturbs ACTA2 filament assembly or stability (Guo 2007).; SCV000738465: Functional studies suggest that this alteration may impact actin assembly (Guo DC et al. Nat. Genet., 2007 Dec;39:1488-93; Bergeron SE et al. J. Biol. Chem., 2011 Apr;286:11356-69).; SCV001733780: Functional studies in yeast and cultured smooth muscle cells have shown that this variant affects actin assembly or stability (PMID:17994018, 21288906).; SCV005203807: Experimental evidence in a yeast background suggests that this variant has significant impacts on actin polymerization and function (example, Bergeron_2011). PMID:23099432, 21288906, 19409525; SCV005900332: "Perturbation of ACTA2 filament assembly/stability has been demonstrated in smooth muscle cells and increased cellular proliferation in myofibroblasts of individuals with this variant (PMID:17994018, 19409525)."". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R118W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACTA2 NM_001613.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.91
• Publications: 23 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 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000287173: Experimental studies have shown that this missense change affects ACTA2 function (PMID: 21288906).; SCV002557626: "This variant has strong functional evidence supporting abnormal protein function. Functional study using smooth muscle cells suggested that variant perturbs ACTA2 filament assembly or stability (PMID: 17994018);"; SCV000710874: Studies on cultured smooth muscle cells (SMCs) derived from a heterozygous carrier of this variant suggest that this variant perturbs ACTA2 filament assembly or stability (Guo 2007).; SCV000738465: Functional studies suggest that this alteration may impact actin assembly (Guo DC et al. Nat. Genet., 2007 Dec;39:1488-93; Bergeron SE et al. J. Biol. Chem., 2011 Apr;286:11356-69).; SCV001733780: Functional studies in yeast and cultured smooth muscle cells have shown that this variant affects actin assembly or stability (PMID: 17994018, 21288906).; SCV005203807: Experimental evidence in a yeast background suggests that this variant has significant impacts on actin polymerization and function (example, Bergeron_2011). PMID: 23099432, 21288906, 19409525; SCV005900332: "Perturbation of ACTA2 filament assembly/stability has been demonstrated in smooth muscle cells and increased cellular proliferation in myofibroblasts of individuals with this variant (PMID: 17994018, 19409525)."
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr10-88943814-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1053987.
• 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 Moyamoya disease 5, connective tissue disorder, multisystemic smooth muscle dysfunction syndrome, familial thoracic aortic aneurysm and aortic dissection, aortic aneurysm, familial thoracic 6.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 10-88943813-C-T is Pathogenic according to our data. Variant chr10-88943813-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 199670.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	NM_001613.4	MANE Select	c.353G>A	p.Arg118Gln	missense	Exon 4 of 9	NP_001604.1	P62736
	ACTA2	NM_001141945.3		c.353G>A	p.Arg118Gln	missense	Exon 4 of 9	NP_001135417.1	D2JYH4
	ACTA2	NM_001320855.2		c.353G>A	p.Arg118Gln	missense	Exon 4 of 9	NP_001307784.1	P62736

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	ENST00000224784.10	TSL:1 MANE Select	c.353G>A	p.Arg118Gln	missense	Exon 4 of 9	ENSP00000224784.6	P62736
	ACTA2	ENST00000713598.1		c.353G>A	p.Arg118Gln	missense	Exon 4 of 9	ENSP00000518894.1	A0AAQ5BGG5
	ACTA2	ENST00000415557.2	TSL:3	c.353G>A	p.Arg118Gln	missense	Exon 4 of 9	ENSP00000396730.2	P62736

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251034 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461514 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727074

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111714

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Familial thoracic aortic aneurysm and aortic dissection (5)
2	-	-	Aortic aneurysm, familial thoracic 6 (2)
1	-	-	Aortic aneurysm, familial thoracic 6;C3151201:Multisystemic smooth muscle dysfunction syndrome;C3279690:Moyamoya disease 5 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.94
Sift4G	Uncertain	0.0070	D
Polyphen		0.94	P
Vest4		0.93
MutPred		0.90		Gain of ubiquitination at K115 (P = 0.0516)
MVP		1.0
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.90
gMVP		0.99
Mutation Taster		=9/91	disease causing (ClinVar)

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: rs112602953; hg19: chr10-90703570; COSMIC: COSV56518008; COSMIC: COSV56518008;