10-88939508-G-A

Variant names:

• chr10-88939508-G-A
• rs112208466
• NM_001613.4:c.807C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001613.4(ACTA2):​c.807C>T​(p.Ile269Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,613,028 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I269I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000070 (1 hom.)
• Consequence: ACTA2 NM_001613.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0009614
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.352
• Publications: 3 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]

STAMBPL1 (HGNC:24105): (STAM binding protein like 1) Predicted to enable Lys63-specific deubiquitinase activity and thiol-dependent deubiquitinase. Predicted to be involved in protein K63-linked deubiquitination. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACTA2-AS1 (HGNC:45169): (ACTA2 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 10-88939508-G-A is Benign according to our data. Variant chr10-88939508-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 380616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.352 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000125 (19/152298) while in subpopulation EAS AF = 0.00212 (11/5182). AF 95% confidence interval is 0.00119. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 19 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001613.4. 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_001613.4	MANE Select	c.807C>T	p.Ile269Ile	splice_region synonymous	Exon 7 of 9	NP_001604.1
	ACTA2	NM_001141945.3		c.807C>T	p.Ile269Ile	splice_region synonymous	Exon 7 of 9	NP_001135417.1
	ACTA2	NM_001320855.2		c.807C>T	p.Ile269Ile	splice_region synonymous	Exon 7 of 9	NP_001307784.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	ENST00000224784.10	TSL:1 MANE Select	c.807C>T	p.Ile269Ile	splice_region synonymous	Exon 7 of 9	ENSP00000224784.6
	ACTA2	ENST00000713598.1		c.849C>T	p.Ile283Ile	splice_region synonymous	Exon 7 of 9	ENSP00000518894.1
	ACTA2	ENST00000415557.2	TSL:3	c.807C>T	p.Ile269Ile	splice_region synonymous	Exon 7 of 9	ENSP00000396730.2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000136 AC: 34 AN: 250854 AF XY: 0.000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00125

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000698 AC: 102 AN: 1460730 Hom.: 1 Cov.: 31 AF XY: 0.0000771 AC XY: 56 AN XY: 726694

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.000134 AC: 6 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00141 AC: 56 AN: 39680

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4968

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1111896

Other (OTH) AF: 0.0000498 AC: 3 AN: 60280

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74460

African (AFR) AF: 0.0000241 AC: 1 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000181 Hom.: 0

Bravo AF: 0.000140

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	1	Aortic aneurysm, familial thoracic 6 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.1
DANN	Benign	0.86
PhyloP100		-0.35
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00096
dbscSNV1_RF	Benign	0.030
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs112208466; hg19: chr10-90699265; COSMIC: COSV56516131; COSMIC: COSV56516131;