rs983751

Variant names:

• chr10-88986936-A-C
• rs983751
• NM_001141945.3:c.-24+4003T>G

Your query was ambiguous. Multiple possible variants found:

• chr10-88986936-A-C
• chr10-88986936-A-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+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
• 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=-0.92).
• 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 rank	MANE	Protein	UniProt
ACTA2	NM_001141945.3	c.-24+4003T>G		intron_variant	Intron 1 of 8		NP_001135417.1
ACTA2	NM_001320855.2	c.-24+4086T>G		intron_variant	Intron 1 of 8		NP_001307784.1
ACTA2	NM_001406462.1	c.-181-1982T>G		intron_variant	Intron 1 of 9		NP_001393391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000415557.2	c.-24+4003T>G		intron_variant	Intron 1 of 8	3		ENSP00000396730.2
ACTA2	ENST00000458159.6	c.-24+4086T>G		intron_variant	Intron 1 of 8	3		ENSP00000398239.2
ACTA2	ENST00000713602.1	c.-181-1982T>G		intron_variant	Intron 1 of 9			ENSP00000518898.1

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

African (AFR) AF: 0.974 AC: 40451 AN: 41540

American (AMR) AF: 0.904 AC: 13826 AN: 15298

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

East Asian (EAS) AF: 0.994 AC: 5160 AN: 5192

South Asian (SAS) AF: 0.889 AC: 4280 AN: 4816

European-Finnish (FIN) AF: 0.849 AC: 9005 AN: 10602

Middle Eastern (MID) AF: 0.873 AC: 255 AN: 292

European-Non Finnish (NFE) AF: 0.862 AC: 58654 AN: 68016

Other (OTH) AF: 0.900 AC: 1905 AN: 2116

Alfa AF: 0.870 Hom.: 24520

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
PhyloP100		-0.31
PromoterAI		-0.0082	Neutral
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: rs983751; hg19: chr10-90746693;