rs111265233

Variant names:

• chr10-88941822-C-T
• rs111265233
• NM_001613.4:c.417G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001613.4(ACTA2):​c.417G>A​(p.Gln139Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000495 in 1,613,270 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: ACTA2 NM_001613.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.07
• 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]

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]

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 10-88941822-C-T is Benign according to our data. Variant chr10-88941822-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 301508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00283 (431/152330) while in subpopulation AFR AF = 0.0101 (420/41584). AF 95% confidence interval is 0.0093. There are 4 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 431 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.417G>A	p.Gln139Gln	synonymous	Exon 5 of 9	NP_001604.1	P62736
	ACTA2	NM_001141945.3		c.417G>A	p.Gln139Gln	synonymous	Exon 5 of 9	NP_001135417.1	D2JYH4
	ACTA2	NM_001320855.2		c.417G>A	p.Gln139Gln	synonymous	Exon 5 of 9	NP_001307784.1	P62736

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	ENST00000224784.10	TSL:1 MANE Select	c.417G>A	p.Gln139Gln	synonymous	Exon 5 of 9	ENSP00000224784.6	P62736
	ACTA2	ENST00000713598.1		c.459G>A	p.Gln153Gln	synonymous	Exon 5 of 9	ENSP00000518894.1	A0AAQ5BGG5
	ACTA2	ENST00000415557.2	TSL:3	c.417G>A	p.Gln139Gln	synonymous	Exon 5 of 9	ENSP00000396730.2	P62736

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 429 AN: 152212 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000678 AC: 169 AN: 249192 AF XY: 0.000431

Gnomad AFR exome AF: 0.00975

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000251 AC: 367 AN: 1460940 Hom.: 1 Cov.: 32 AF XY: 0.000209 AC XY: 152 AN XY: 726678

African (AFR) AF: 0.00932 AC: 312 AN: 33468

American (AMR) AF: 0.000246 AC: 11 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39534

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 86012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111672

Other (OTH) AF: 0.000563 AC: 34 AN: 60360

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152330 Hom.: 4 Cov.: 32 AF XY: 0.00263 AC XY: 196 AN XY: 74482

African (AFR) AF: 0.0101 AC: 420 AN: 41584

American (AMR) AF: 0.000588 AC: 9 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00195 Hom.: 3

Bravo AF: 0.00286

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Familial thoracic aortic aneurysm and aortic dissection (5)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Aortic aneurysm, familial thoracic 6 (1)
-	-	1	Moyamoya disease (1)
-	-	1	Multisystemic smooth muscle dysfunction syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		2.1
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs111265233; hg19: chr10-90701579;