1-229432190-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_001100.4(ACTA1):c.617-5C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001100.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTA1 | NM_001100.4 | c.617-5C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000366684.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTA1 | ENST00000366684.7 | c.617-5C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_001100.4 | P1 | |||
ACTA1 | ENST00000366683.4 | c.617-5C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 5 | |||||
ACTA1 | ENST00000684723.1 | c.482-5C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 13, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2021 | Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 19562689) - |
Actin accumulation myopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2021 | This sequence change falls in intron 4 of the ACTA1 gene. It does not directly change the encoded amino acid sequence of the ACTA1 protein. This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1051987). This variant has been observed in individuals with autosomal dominant nemaline myopathy (PMID: 19562689; Invitae). It has also been observed to segregate with disease in related individuals. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.