rs553556054

Variant names:

• chr10-88990523-TCC-T
• rs553556054
• NM_001141945.3:c.-24+414_-24+415delGG

Your query was ambiguous. Multiple possible variants found:

• chr10-88990523-TCC-T
• chr10-88990523-TCC-TC
• chr10-88990523-TCC-TCCC

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 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 type 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autoimmune lymphoproliferative syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet

ENSG00000286116 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 518 AD,Unknown gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	NM_001141945.3		c.-24+414_-24+415delGG		intron	N/A	NP_001135417.1	D2JYH4
	ACTA2	NM_001320855.2		c.-24+497_-24+498delGG		intron	N/A	NP_001307784.1	P62736
	ACTA2	NM_001406462.1		c.-182+497_-182+498delGG		intron	N/A	NP_001393391.1	P62736

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	ENST00000415557.2	TSL:3	c.-24+414_-24+415delGG		intron	N/A	ENSP00000396730.2	P62736
	ACTA2	ENST00000458159.6	TSL:3	c.-24+497_-24+498delGG		intron	N/A	ENSP00000398239.2	P62736
	ACTA2	ENST00000713602.1		c.-182+497_-182+498delGG		intron	N/A	ENSP00000518898.1	P62736

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

GnomAD2 exomes AF: 0.00322 AC: 419 AN: 130030 AF XY: 0.00327

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 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

African (AFR) AF: 0.000494 AC: 7 AN: 14164

American (AMR) AF: 0.00424 AC: 134 AN: 31590

Ashkenazi Jewish (ASJ) AF: 0.00650 AC: 115 AN: 17700

East Asian (EAS) AF: 0.00 AC: 0 AN: 24472

South Asian (SAS) AF: 0.0000656 AC: 4 AN: 60976

European-Finnish (FIN) AF: 0.00149 AC: 32 AN: 21468

Middle Eastern (MID) AF: 0.00391 AC: 8 AN: 2046

European-Non Finnish (NFE) AF: 0.00468 AC: 1190 AN: 254316

Other (OTH) AF: 0.00441 AC: 110 AN: 24954

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

African (AFR) AF: 0.000772 AC: 32 AN: 41434

American (AMR) AF: 0.00760 AC: 116 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00693 AC: 24 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4804

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10574

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00469 AC: 319 AN: 67978

Other (OTH) AF: 0.00427 AC: 9 AN: 2106

Alfa AF: 0.00611 Hom.: 0

Bravo AF: 0.00378

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Autoimmune lymphoproliferative syndrome type 1 (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Moyamoya disease (1)
-	-	1	Multisystemic smooth muscle dysfunction syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.98
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs553556054; hg19: chr10-90750280;