10-88990530-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000651408.1(ENSG00000286116):n.3720G>A 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 0.0035 in 612,960 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (6 hom.)
• Consequence: ENST00000651408.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:4
• Conservation: PhyloP100: -0.531

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 10-88990530-C-T is Benign according to our data. Variant chr10-88990530-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 301515.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTA2	NM_001141945.3	c.-24+409G>A		intron_variant
ACTA2	NM_001320855.2	c.-24+492G>A		intron_variant
ACTA2	NM_001406462.1	c.-182+492G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
	ENST00000651408.1	n.3720G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 521 AN: 152202 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00473

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00324 AC: 422 AN: 130388 Hom.: 1 AF XY: 0.00329 AC XY: 234 AN XY: 71112

Gnomad AFR exome AF: 0.000324

Gnomad AMR exome AF: 0.00452

Gnomad ASJ exome AF: 0.00679

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000893

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00453

Gnomad OTH exome AF: 0.00572

GnomAD4 exome AF: 0.00353 AC: 1628 AN: 460640 Hom.: 6 Cov.: 0 AF XY: 0.00342 AC XY: 855 AN XY: 250150

Gnomad4 AFR exome AF: 0.000488

Gnomad4 AMR exome AF: 0.00421

Gnomad4 ASJ exome AF: 0.00646

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000655

Gnomad4 FIN exome AF: 0.00142

Gnomad4 NFE exome AF: 0.00468

Gnomad4 OTH exome AF: 0.00432

GnomAD4 genome AF: 0.00341 AC: 519 AN: 152320 Hom.: 2 Cov.: 32 AF XY: 0.00336 AC XY: 250 AN XY: 74474

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00758

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00470

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00603 Hom.: 0

Bravo AF: 0.00378

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Moyamoya disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Multisystemic smooth muscle dysfunction syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autoimmune lymphoproliferative syndrome type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	5.0
Dann	Benign	0.91

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs56220100; hg19: chr10-90750287;