10-88948798-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001613.4(ACTA2):c.129+4A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,590 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 Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
ACTA2
NM_001613.4 splice_donor_region, intron
NM_001613.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9987
2
Clinical Significance
Conservation
PhyloP100: 1.60
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTA2 | NM_001613.4 | c.129+4A>G | splice_donor_region_variant, intron_variant | ENST00000224784.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTA2 | ENST00000224784.10 | c.129+4A>G | splice_donor_region_variant, intron_variant | 1 | NM_001613.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251004Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135652
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461590Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727098
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Aortic aneurysm, familial thoracic 6;C3151201:Multisystemic smooth muscle dysfunction syndrome;C3279690:Moyamoya disease 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 01, 2022 | - - |
Aortic aneurysm, familial thoracic 6 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 16, 2017 | In summary, this is a novel intronic change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ACTA2-related disease. This sequence change falls in intron 2 of the ACTA2 gene. It does not directly change the encoded amino acid sequence of the ACTA2 protein, but it affects a nucleotide within the consensus splice site of the intron. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at