chr10-88990530-C-T

Variant names:

• chr10-88990530-C-T
• rs56220100
• NM_001141945.3:c.-24+409G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001141945.3(ACTA2):​c.-24+409G>A variant causes a intron 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: ACTA2 NM_001141945.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.531
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autoimmune lymphoproliferative syndrome

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

ENSG00000286116 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 301515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00341 (519/152320) while in subpopulation AMR AF = 0.00758 (116/15304). AF 95% confidence interval is 0.00646. There are 2 homozygotes in GnomAd4. There are 250 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 519 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+409G>A		intron	N/A	NP_001135417.1	D2JYH4
	ACTA2	NM_001320855.2		c.-24+492G>A		intron	N/A	NP_001307784.1	P62736
	ACTA2	NM_001406462.1		c.-182+492G>A		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+409G>A		intron	N/A	ENSP00000396730.2	P62736
	ACTA2	ENST00000458159.6	TSL:3	c.-24+492G>A		intron	N/A	ENSP00000398239.2	P62736
	ACTA2	ENST00000713602.1		c.-182+492G>A		intron	N/A	ENSP00000518898.1	P62736

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

GnomAD2 exomes AF: 0.00324 AC: 422 AN: 130388 AF XY: 0.00329

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 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

African (AFR) AF: 0.000488 AC: 7 AN: 14352

American (AMR) AF: 0.00421 AC: 134 AN: 31808

Ashkenazi Jewish (ASJ) AF: 0.00646 AC: 116 AN: 17958

East Asian (EAS) AF: 0.00 AC: 0 AN: 25108

South Asian (SAS) AF: 0.0000655 AC: 4 AN: 61090

European-Finnish (FIN) AF: 0.00142 AC: 32 AN: 22520

Middle Eastern (MID) AF: 0.00383 AC: 8 AN: 2088

European-Non Finnish (NFE) AF: 0.00468 AC: 1217 AN: 260240

Other (OTH) AF: 0.00432 AC: 110 AN: 25476

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

African (AFR) AF: 0.000770 AC: 32 AN: 41580

American (AMR) AF: 0.00758 AC: 116 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00470 AC: 320 AN: 68026

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00603 Hom.: 0

Bravo AF: 0.00378

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.0
DANN	Benign	0.91
PhyloP100		-0.53
PromoterAI		-0.14	Neutral
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: rs56220100; hg19: chr10-90750287;