10-88935118-C-A

Variant names:

• chr10-88935118-C-A
• rs149059995
• NM_001613.4:c.*105G>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001613.4(ACTA2):​c.*105G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000859 in 1,505,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (0 hom.)
• Consequence: ACTA2 NM_001613.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0410
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 10-88935118-C-A is Benign according to our data. Variant chr10-88935118-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 301504.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00065 (99/152236) while in subpopulation NFE AF = 0.000706 (48/68014). AF 95% confidence interval is 0.000547. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 99 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.*105G>T		3_prime_UTR	Exon 9 of 9	NP_001604.1	P62736
	ACTA2	NM_001141945.3		c.*105G>T		3_prime_UTR	Exon 9 of 9	NP_001135417.1	D2JYH4
	ACTA2	NM_001320855.2		c.*105G>T		3_prime_UTR	Exon 9 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.*105G>T		3_prime_UTR	Exon 9 of 9	ENSP00000224784.6	P62736
	ACTA2	ENST00000713598.1		c.*105G>T		3_prime_UTR	Exon 9 of 9	ENSP00000518894.1	A0AAQ5BGG5
	ACTA2	ENST00000415557.2	TSL:3	c.*105G>T		3_prime_UTR	Exon 9 of 9	ENSP00000396730.2	P62736

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00406

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000882 AC: 1194 AN: 1353008 Hom.: 0 Cov.: 19 AF XY: 0.000834 AC XY: 562 AN XY: 673824

African (AFR) AF: 0.000194 AC: 6 AN: 30966

American (AMR) AF: 0.000164 AC: 7 AN: 42798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24100

East Asian (EAS) AF: 0.00 AC: 0 AN: 38318

South Asian (SAS) AF: 0.00 AC: 0 AN: 81818

European-Finnish (FIN) AF: 0.00464 AC: 238 AN: 51280

Middle Eastern (MID) AF: 0.000262 AC: 1 AN: 3824

European-Non Finnish (NFE) AF: 0.000883 AC: 904 AN: 1023922

Other (OTH) AF: 0.000679 AC: 38 AN: 55982

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000699 AC XY: 52 AN XY: 74436

African (AFR) AF: 0.000169 AC: 7 AN: 41534

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00406 AC: 43 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000424 Hom.: 0

Bravo AF: 0.000397

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Aortic aneurysm, familial thoracic 6 (1)
-	-	1	Multisystemic smooth muscle dysfunction syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.9
DANN	Benign	0.78
PhyloP100		0.041
Mutation Taster		=100/0	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: rs149059995; hg19: chr10-90694875;