10-88983584-G-A

Variant names:

• chr10-88983584-G-A
• rs7910825
• NM_001141945.3:c.-24+7355C>T

Variant summary

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

The NM_001141945.3(ACTA2):​c.-24+7355C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.57 (21461 hom., cov: 17)
• Consequence: ACTA2 NM_001141945.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.594
• Publications: 16 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]

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]

FAS Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• autoimmune lymphoproliferative syndrome type 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA2	NM_001141945.3	c.-24+7355C>T		intron_variant	Intron 1 of 8		NP_001135417.1
ACTA2	NM_001320855.2	c.-24+7438C>T		intron_variant	Intron 1 of 8		NP_001307784.1
ACTA2	NM_001406462.1	c.-24+1213C>T		intron_variant	Intron 2 of 9		NP_001393391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000415557.2	c.-24+7355C>T		intron_variant	Intron 1 of 8	3		ENSP00000396730.2
ACTA2	ENST00000458159.6	c.-24+7438C>T		intron_variant	Intron 1 of 8	3		ENSP00000398239.2
ACTA2	ENST00000713602.1	c.-24+1213C>T		intron_variant	Intron 2 of 9			ENSP00000518898.1

Frequencies

GnomAD3 genomes AF: 0.572 AC: 72826 AN: 127290 Hom.: 21429 Cov.: 17

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.600

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.516

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.580

Gnomad MID AF: 0.618

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.550

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

GnomAD4 genome AF: 0.572 AC: 72892 AN: 127356 Hom.: 21461 Cov.: 17 AF XY: 0.582 AC XY: 34617 AN XY: 59508

African (AFR) AF: 0.783 AC: 26912 AN: 34382

American (AMR) AF: 0.601 AC: 6750 AN: 11230

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1385 AN: 3308

East Asian (EAS) AF: 0.516 AC: 2105 AN: 4082

South Asian (SAS) AF: 0.476 AC: 1829 AN: 3844

European-Finnish (FIN) AF: 0.580 AC: 2758 AN: 4758

Middle Eastern (MID) AF: 0.618 AC: 126 AN: 204

European-Non Finnish (NFE) AF: 0.471 AC: 29657 AN: 62968

Other (OTH) AF: 0.553 AC: 955 AN: 1728

Alfa AF: 0.478 Hom.: 7753

Bravo AF: 0.565

Asia WGS AF: 0.528 AC: 1830 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.0
DANN	Benign	0.29
PhyloP100		0.59
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: rs7910825; hg19: chr10-90743341;