rs7916294

Variant names:

• chr10-88984568-C-A
• rs7916294
• NM_001141945.3:c.-24+6371G>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+6371G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 152,090 control chromosomes in the GnomAD database, including 10,728 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 0.36 (10728 hom., cov: 33)
• Consequence: ACTA2 NM_001141945.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.45
• Publications: 12 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.486 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+6371G>T		intron	N/A	NP_001135417.1	D2JYH4
	ACTA2	NM_001320855.2		c.-24+6454G>T		intron	N/A	NP_001307784.1	P62736
	ACTA2	NM_001406462.1		c.-24+229G>T		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+6371G>T		intron	N/A	ENSP00000396730.2	P62736
	ACTA2	ENST00000458159.6	TSL:3	c.-24+6454G>T		intron	N/A	ENSP00000398239.2	P62736
	ACTA2	ENST00000713602.1		c.-24+229G>T		intron	N/A	ENSP00000518898.1	P62736

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54642 AN: 151972 Hom.: 10706 Cov.: 33

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.0217

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.335

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

GnomAD4 genome AF: 0.360 AC: 54726 AN: 152090 Hom.: 10728 Cov.: 33 AF XY: 0.357 AC XY: 26501 AN XY: 74332

African (AFR) AF: 0.492 AC: 20403 AN: 41458

American (AMR) AF: 0.337 AC: 5151 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 960 AN: 3466

East Asian (EAS) AF: 0.0216 AC: 112 AN: 5188

South Asian (SAS) AF: 0.206 AC: 995 AN: 4824

European-Finnish (FIN) AF: 0.330 AC: 3486 AN: 10562

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22541 AN: 67994

Other (OTH) AF: 0.338 AC: 712 AN: 2108

Alfa AF: 0.346 Hom.: 11998

Bravo AF: 0.369

Asia WGS AF: 0.164 AC: 570 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.12
DANN	Benign	0.51
PhyloP100		-2.5
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: rs7916294; hg19: chr10-90744325;