rs753923758
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001100.4(ACTA1):c.84_85insT(p.Pro29SerfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
ACTA1
NM_001100.4 frameshift
NM_001100.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.747
Genes affected
ACTA1 (HGNC:129): (actin alpha 1, skeletal muscle) The product encoded by this gene belongs to the actin family of proteins, which are highly conserved proteins that play a role in cell motility, structure and integrity. Alpha, beta and gamma actin isoforms have been identified, with alpha actins being a major constituent of the contractile apparatus, while beta and gamma actins are involved in the regulation of cell motility. This actin is an alpha actin that is found in skeletal muscle. Mutations in this gene cause a variety of myopathies, including nemaline myopathy, congenital myopathy with excess of thin myofilaments, congenital myopathy with cores, and congenital myopathy with fiber-type disproportion, diseases that lead to muscle fiber defects with manifestations such as hypotonia. [provided by RefSeq, Sep 2019]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 473 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-229433031-G-GA is Pathogenic according to our data. Variant chr1-229433031-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 464132.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTA1 | NM_001100.4 | c.84_85insT | p.Pro29SerfsTer2 | frameshift_variant | 2/7 | ENST00000366684.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTA1 | ENST00000366684.7 | c.84_85insT | p.Pro29SerfsTer2 | frameshift_variant | 2/7 | 1 | NM_001100.4 | P1 | |
ACTA1 | ENST00000366683.4 | c.84_85insT | p.Pro29SerfsTer2 | frameshift_variant | 2/7 | 5 | |||
ACTA1 | ENST00000684723.1 | c.-6-152_-6-151insT | intron_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250244Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135504
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461544Hom.: 0 Cov.: 38 AF XY: 0.00000275 AC XY: 2AN XY: 727080
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Actin accumulation myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 23, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 464132). This variant has not been reported in the literature in individuals affected with ACTA1-related conditions. This variant is present in population databases (rs753923758, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Pro29Serfs*2) in the ACTA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACTA1 are known to be pathogenic (PMID: 19562689). - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at