XM_011539764.3:c.-1430T>A

Variant names:

• chr10-88981502-T-A
• rs6586161
• XM_011539764.3:c.-1430T>A

Variant summary

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

The XM_011539764.3(FAS):​c.-1430T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 151,910 control chromosomes in the GnomAD database, including 7,313 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 0.26 (7313 hom., cov: 31)
• Consequence: FAS XM_011539764.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.542
• Publications: 10 publications found

Genes affected

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]

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]

ACTA2 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• multisystemic smooth muscle dysfunction syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• aortic aneurysm, familial thoracic 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• Moyamoya disease 5

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
• connective tissue disorder

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000415557.2. 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+9437A>T		intron	N/A	NP_001135417.1
	ACTA2	NM_001320855.2		c.-24+9520A>T		intron	N/A	NP_001307784.1
	ACTA2	NM_001406462.1		c.-24+3295A>T		intron	N/A	NP_001393391.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	ENST00000415557.2	TSL:3	c.-24+9437A>T		intron	N/A	ENSP00000396730.2
	ACTA2	ENST00000458159.6	TSL:3	c.-24+9520A>T		intron	N/A	ENSP00000398239.2
	ACTA2	ENST00000713602.1		c.-24+3295A>T		intron	N/A	ENSP00000518898.1

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40132 AN: 151792 Hom.: 7291 Cov.: 31

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.254

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

GnomAD4 genome AF: 0.265 AC: 40207 AN: 151910 Hom.: 7313 Cov.: 31 AF XY: 0.263 AC XY: 19556 AN XY: 74250

African (AFR) AF: 0.501 AC: 20734 AN: 41354

American (AMR) AF: 0.232 AC: 3533 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 537 AN: 3466

East Asian (EAS) AF: 0.451 AC: 2324 AN: 5154

South Asian (SAS) AF: 0.242 AC: 1169 AN: 4822

European-Finnish (FIN) AF: 0.137 AC: 1444 AN: 10558

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9709 AN: 67992

Other (OTH) AF: 0.254 AC: 534 AN: 2104

Alfa AF: 0.194 Hom.: 562

Bravo AF: 0.279

Asia WGS AF: 0.396 AC: 1377 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.6
DANN	Benign	0.80
PhyloP100		0.54
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: rs6586161; hg19: chr10-90741259;