rs978522

Positions:

• chr10-88988581-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001141945.3(ACTA2):​c.-24+2358A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 151,944 control chromosomes in the GnomAD database, including 10,196 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 0.35 (10196 hom., cov: 30)
• Consequence: ACTA2 NM_001141945.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.319

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]

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA2	NM_001141945.3	c.-24+2358A>G		intron_variant			NP_001135417.1
ACTA2	NM_001320855.2	c.-24+2441A>G		intron_variant			NP_001307784.1
ACTA2	NM_001406462.1	c.-182+2441A>G		intron_variant			NP_001393391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000415557.2	c.-24+2358A>G		intron_variant		3		ENSP00000396730	P1
ACTA2	ENST00000458159.6	c.-24+2441A>G		intron_variant		3		ENSP00000398239	P1
FAS	ENST00000690268.1	c.-1+491T>C		intron_variant				ENSP00000509810	A2

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53488 AN: 151826 Hom.: 10196 Cov.: 30

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.372

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

GnomAD4 genome AF: 0.352 AC: 53490 AN: 151944 Hom.: 10196 Cov.: 30 AF XY: 0.355 AC XY: 26368 AN XY: 74286

Gnomad4 AFR AF: 0.203

Gnomad4 AMR AF: 0.368

Gnomad4 ASJ AF: 0.454

Gnomad4 EAS AF: 0.523

Gnomad4 SAS AF: 0.454

Gnomad4 FIN AF: 0.396

Gnomad4 NFE AF: 0.406

Gnomad4 OTH AF: 0.370

Alfa AF: 0.379 Hom.: 1434

Bravo AF: 0.344

Asia WGS AF: 0.416 AC: 1443 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.8
DANN	Benign	0.83

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs978522; hg19: chr10-90748338;