10-88967577-C-A

Variant names:

• chr10-88967577-C-A
• rs1926203
• XM_006717819.4:c.-5771C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001141945.3(ACTA2):​c.-23-18624G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.578 in 152,026 control chromosomes in the GnomAD database, including 26,555 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.58 (26555 hom., cov: 32)
• Consequence: ACTA2 NM_001141945.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.560
• Publications: 24 publications found

Genes affected

FAS (HGNC:11920): (Fas cell surface death receptor) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contains a death domain. It has been shown to play a central role in the physiological regulation of programmed cell death, and has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The interaction of this receptor with its ligand allows the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10. The autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, and leads to apoptosis. This receptor has been also shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is found to be involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Several alternatively spliced transcript variants have been described, some of which are candidates for nonsense-mediated mRNA decay (NMD). The isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform. [provided by RefSeq, Mar 2011]

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 (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 Gene-Disease associations (from GenCC):

• multisystemic smooth muscle dysfunction syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• aortic aneurysm, familial thoracic 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Moyamoya disease 5

  Inheritance: AD Classification: STRONG Submitted by: G2P, Genomics England PanelApp
• connective tissue disorder

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001141945.3. 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_001141945.3		c.-23-18624G>T		intron	N/A	NP_001135417.1	D2JYH4
	ACTA2	NM_001320855.2		c.-23-18624G>T		intron	N/A	NP_001307784.1	P62736
	ACTA2	NM_001406462.1		c.-24+17220G>T		intron	N/A	NP_001393391.1	P62736

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAMBPL1	ENST00000371927.7	TSL:2	c.1255-5605C>A		intron	N/A	ENSP00000360995.3	Q96FJ0-2
	ACTA2	ENST00000415557.2	TSL:3	c.-23-18624G>T		intron	N/A	ENSP00000396730.2	P62736
	ACTA2	ENST00000458159.6	TSL:3	c.-23-18624G>T		intron	N/A	ENSP00000398239.2	P62736

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87813 AN: 151908 Hom.: 26530 Cov.: 32

Gnomad AFR AF: 0.561

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.617

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.557

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.578 AC: 87884 AN: 152026 Hom.: 26555 Cov.: 32 AF XY: 0.566 AC XY: 42033 AN XY: 74316

African (AFR) AF: 0.562 AC: 23295 AN: 41464

American (AMR) AF: 0.479 AC: 7307 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1751 AN: 3464

East Asian (EAS) AF: 0.136 AC: 702 AN: 5176

South Asian (SAS) AF: 0.273 AC: 1314 AN: 4822

European-Finnish (FIN) AF: 0.617 AC: 6517 AN: 10570

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.665 AC: 45151 AN: 67944

Other (OTH) AF: 0.555 AC: 1173 AN: 2114

Alfa AF: 0.630 Hom.: 136483

Bravo AF: 0.571

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.79
DANN	Benign	0.47
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1926203; hg19: chr10-90727334;