NM_001141945.3:c.-24+11749T>A

Variant names:

• chr10-88979190-A-T
• rs17447140
• NM_001141945.3:c.-24+11749T>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+11749T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 151,860 control chromosomes in the GnomAD database, including 13,188 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 0.39 (13188 hom., cov: 30)
• Consequence: ACTA2 NM_001141945.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.565
• Publications: 5 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	NM_001141945.3		c.-24+11749T>A		intron	N/A	NP_001135417.1
	ACTA2	NM_001320855.2		c.-24+11832T>A		intron	N/A	NP_001307784.1
	ACTA2	NM_001406462.1		c.-24+5607T>A		intron	N/A	NP_001393391.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	ENST00000415557.2	TSL:3	c.-24+11749T>A		intron	N/A	ENSP00000396730.2
	ACTA2	ENST00000458159.6	TSL:3	c.-24+11832T>A		intron	N/A	ENSP00000398239.2
	ACTA2	ENST00000713602.1		c.-24+5607T>A		intron	N/A	ENSP00000518898.1

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59497 AN: 151740 Hom.: 13183 Cov.: 30

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.404

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

GnomAD4 genome AF: 0.392 AC: 59525 AN: 151860 Hom.: 13188 Cov.: 30 AF XY: 0.394 AC XY: 29264 AN XY: 74232

African (AFR) AF: 0.198 AC: 8204 AN: 41390

American (AMR) AF: 0.430 AC: 6568 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1245 AN: 3472

East Asian (EAS) AF: 0.226 AC: 1170 AN: 5168

South Asian (SAS) AF: 0.302 AC: 1455 AN: 4816

European-Finnish (FIN) AF: 0.610 AC: 6415 AN: 10520

Middle Eastern (MID) AF: 0.397 AC: 116 AN: 292

European-Non Finnish (NFE) AF: 0.491 AC: 33325 AN: 67918

Other (OTH) AF: 0.400 AC: 845 AN: 2114

Alfa AF: 0.432 Hom.: 1883

Bravo AF: 0.374

Asia WGS AF: 0.259 AC: 903 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		-0.56
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: rs17447140; hg19: chr10-90738947;