10-88990523-TCC-T

Position:

• chr10-88990523-TCC-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001141945.3(ACTA2):​c.-24+414_-24+415delGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00351 in 603,672 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (6 hom.)
• Consequence: ACTA2 NM_001141945.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 0.981

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]

ENSG00000286116 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 10-88990523-TCC-T is Benign according to our data. Variant chr10-88990523-TCC-T is described in ClinVar as [Likely_benign]. Clinvar id is 301514.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00341 (518/151986) while in subpopulation AMR AF= 0.0076 (116/15270). AF 95% confidence interval is 0.00647. There are 2 homozygotes in gnomad4. There are 249 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 518 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTA2	NM_001141945.3	c.-24+414_-24+415delGG		intron_variant			NP_001135417.1
ACTA2	NM_001320855.2	c.-24+497_-24+498delGG		intron_variant			NP_001307784.1
ACTA2	NM_001406462.1	c.-182+497_-182+498delGG		intron_variant			NP_001393391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000415557.2	c.-24+414_-24+415delGG		intron_variant		3		ENSP00000396730.2
ACTA2	ENST00000458159.6	c.-24+497_-24+498delGG		intron_variant		3		ENSP00000398239.2
FAS	ENST00000690268.1	c.111+948_111+949delCC		intron_variant				ENSP00000509810.1

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 520 AN: 151868 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00761

Gnomad ASJ AF: 0.00693

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00472

Gnomad OTH AF: 0.00432

GnomAD3 exomes AF: 0.00322 AC: 419 AN: 130030 Hom.: 1 AF XY: 0.00327 AC XY: 232 AN XY: 70898

Gnomad AFR exome AF: 0.000324

Gnomad AMR exome AF: 0.00452

Gnomad ASJ exome AF: 0.00681

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000894

Gnomad FIN exome AF: 0.00112

Gnomad NFE exome AF: 0.00450

Gnomad OTH exome AF: 0.00573

GnomAD4 exome AF: 0.00354 AC: 1600 AN: 451686 Hom.: 6 AF XY: 0.00342 AC XY: 839 AN XY: 245356

Gnomad4 AFR exome AF: 0.000494

Gnomad4 AMR exome AF: 0.00424

Gnomad4 ASJ exome AF: 0.00650

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000656

Gnomad4 FIN exome AF: 0.00149

Gnomad4 NFE exome AF: 0.00468

Gnomad4 OTH exome AF: 0.00441

GnomAD4 genome AF: 0.00341 AC: 518 AN: 151986 Hom.: 2 Cov.: 33 AF XY: 0.00335 AC XY: 249 AN XY: 74304

Gnomad4 AFR AF: 0.000772

Gnomad4 AMR AF: 0.00760

Gnomad4 ASJ AF: 0.00693

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00469

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00611 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs553556054; hg19: chr10-90750280;