rs983751

chr10-88986936-A-Cchr10-88986936-A-T

Variant summary

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

The NM_001141945.3(ACTA2):c.-24+4003T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.902 in 152,256 control chromosomes in the GnomAD database, including 62,198 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 0.90 (62198 hom., cov: 32)
• Consequence: ACTA2 NM_001141945.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.306

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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTA2	NM_001141945.3	c.-24+4003T>G		intron_variant
ACTA2	NM_001320855.2	c.-24+4086T>G		intron_variant
ACTA2	NM_001406462.1	c.-181-1982T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTA2	ENST00000415557.2	c.-24+4003T>G		intron_variant		3		P1
ACTA2	ENST00000458159.6	c.-24+4086T>G		intron_variant		3		P1
FAS	ENST00000690268.1	c.-175+131A>C		intron_variant				A2

Frequencies

GnomAD3 genomes AF: 0.902 AC: 137230 AN: 152138 Hom.: 62132 Cov.: 32

Gnomad AFR AF: 0.974

Gnomad AMI AF: 0.900

Gnomad AMR AF: 0.904

Gnomad ASJ AF: 0.864

Gnomad EAS AF: 0.994

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.849

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.862

Gnomad OTH AF: 0.899

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

GnomAD4 genome AF: 0.902 AC: 137357 AN: 152256 Hom.: 62198 Cov.: 32 AF XY: 0.903 AC XY: 67235 AN XY: 74438

Gnomad4 AFR AF: 0.974

Gnomad4 AMR AF: 0.904

Gnomad4 ASJ AF: 0.864

Gnomad4 EAS AF: 0.994

Gnomad4 SAS AF: 0.889

Gnomad4 FIN AF: 0.849

Gnomad4 NFE AF: 0.862

Gnomad4 OTH AF: 0.900

Alfa AF: 0.870 Hom.: 21258

Bravo AF: 0.909

Asia WGS AF: 0.950 AC: 3302 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	3.7
Dann	Benign	0.84

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs983751; hg19: chr10-90746693;