10-88990206-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000651408.1(ENSG00000286116):n.4044T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 152,064 control chromosomes in the GnomAD database, including 22,963 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.54 (22963 hom., cov: 32)
• Consequence: ENST00000651408.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0250

Genes affected

(HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-88990206-A-G is Benign according to our data. Variant chr10-88990206-A-G is described in ClinVar as [Benign]. Clinvar id is 779595.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTA2	NM_001141945.3	c.-24+733T>C		intron_variant
ACTA2	NM_001320855.2	c.-24+816T>C		intron_variant
ACTA2	NM_001406462.1	c.-182+816T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
	ENST00000651408.1	n.4044T>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.536 AC: 81399 AN: 151942 Hom.: 22905 Cov.: 32

Gnomad AFR AF: 0.721

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.513

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

GnomAD4 genome AF: 0.536 AC: 81523 AN: 152064 Hom.: 22963 Cov.: 32 AF XY: 0.535 AC XY: 39759 AN XY: 74334

Gnomad4 AFR AF: 0.721

Gnomad4 AMR AF: 0.531

Gnomad4 ASJ AF: 0.411

Gnomad4 EAS AF: 0.472

Gnomad4 SAS AF: 0.434

Gnomad4 FIN AF: 0.450

Gnomad4 NFE AF: 0.458

Gnomad4 OTH AF: 0.516

Alfa AF: 0.474 Hom.: 30424

Bravo AF: 0.550

Asia WGS AF: 0.533 AC: 1854 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	5.1
Dann	Benign	0.54

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1800682; hg19: chr10-90749963;