10-88938111-G-C

Variant names:

• chr10-88938111-G-C
• rs886038978
• NM_001613.4:c.940C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The ENST00000224784.10(ACTA2):​c.940C>G​(p.Arg314Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R314Q) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ACTA2 ENST00000224784.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.15
• Publications: 6 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]

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

ACMG classification

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

• 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: MetaRNN computational evidence supports a deleterious effect, 0.993

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000224784.10. 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.940C>G	p.Arg314Gly	missense	Exon 8 of 9	NP_001604.1
	ACTA2	NM_001141945.3		c.940C>G	p.Arg314Gly	missense	Exon 8 of 9	NP_001135417.1
	ACTA2	NM_001320855.2		c.940C>G	p.Arg314Gly	missense	Exon 8 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.940C>G	p.Arg314Gly	missense	Exon 8 of 9	ENSP00000224784.6
	ACTA2	ENST00000713598.1		c.982C>G	p.Arg328Gly	missense	Exon 8 of 9	ENSP00000518894.1
	ACTA2	ENST00000415557.2	TSL:3	c.940C>G	p.Arg314Gly	missense	Exon 8 of 9	ENSP00000396730.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152054 Hom.: 0 Cov.: 32

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 Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74268

African (AFR) AF: 0.00 AC: 0 AN: 41390

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	5.5	H
PhyloP100		2.1
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.91
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.90		Gain of catalytic residue at Q316 (P = 0.0758)
MVP		1.0
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.99
gMVP		0.99
Mutation Taster		=9/91	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: rs886038978; hg19: chr10-90697868;