chr10-88988979-C-T

Variant names:

• chr10-88988979-C-T
• rs3758483
• NM_001141945.3:c.-24+1960G>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.-24+1960G>A 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 152,268 control chromosomes in the GnomAD database, including 62,195 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 (62195 hom., cov: 32)
• Consequence: ACTA2 NM_001141945.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.900
• Publications: 22 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 type 1

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

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 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.-24+1960G>A		intron	N/A	NP_001135417.1	D2JYH4
	ACTA2	NM_001320855.2		c.-24+2043G>A		intron	N/A	NP_001307784.1	P62736
	ACTA2	NM_001406462.1		c.-182+2043G>A		intron	N/A	NP_001393391.1	P62736

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	ENST00000415557.2	TSL:3	c.-24+1960G>A		intron	N/A	ENSP00000396730.2	P62736
	ACTA2	ENST00000458159.6	TSL:3	c.-24+2043G>A		intron	N/A	ENSP00000398239.2	P62736
	ACTA2	ENST00000713602.1		c.-182+2043G>A		intron	N/A	ENSP00000518898.1	P62736

Frequencies

GnomAD3 genomes AF: 0.902 AC: 137234 AN: 152150 Hom.: 62129 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: 0.887

Gnomad FIN AF: 0.849

Gnomad MID AF: 0.867

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: 137361 AN: 152268 Hom.: 62195 Cov.: 32 AF XY: 0.903 AC XY: 67230 AN XY: 74434

African (AFR) AF: 0.974 AC: 40473 AN: 41568

American (AMR) AF: 0.904 AC: 13827 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.864 AC: 3000 AN: 3472

East Asian (EAS) AF: 0.994 AC: 5154 AN: 5186

South Asian (SAS) AF: 0.888 AC: 4290 AN: 4832

European-Finnish (FIN) AF: 0.849 AC: 8986 AN: 10582

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.862 AC: 58652 AN: 68008

Other (OTH) AF: 0.900 AC: 1903 AN: 2114

Alfa AF: 0.878 Hom.: 97242

Bravo AF: 0.909

Asia WGS AF: 0.950 AC: 3303 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.14
DANN	Benign	0.34
PhyloP100		-0.90
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: rs3758483; hg19: chr10-90748736;