rs372686280
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_001100.4(ACTA1):c.990+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001100.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTA1 | NM_001100.4 | c.990+1G>T | splice_donor_variant | ENST00000366684.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTA1 | ENST00000366684.7 | c.990+1G>T | splice_donor_variant | 1 | NM_001100.4 | P1 | |||
ENST00000702606.1 | n.355C>A | non_coding_transcript_exon_variant | 1/1 | ||||||
ACTA1 | ENST00000366683.4 | c.990+1G>T | splice_donor_variant | 5 | |||||
ACTA1 | ENST00000684723.1 | c.855+1G>T | splice_donor_variant |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251344Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135884
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461862Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727236
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74352
ClinVar
Submissions by phenotype
Actin accumulation myopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 30, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 24, 2016 | This sequence change affects a donor splice site in the last intron (intron 6) of the ACTA1 gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This variant has been reported in an individual affected with severe nemaline myopathy. It was reported to occur in trans with a pathogenic variant (p.Tyr190*) and to be inherited in an autosomal recessive manner (PMID: 19562689). This variant has also been reported in trans with another pathogenic variant (p.Ala146Profs*46) in a second individual affected with nemaline myopathy (http://www.dmd.nl/nmdb). Truncating mutations in ACTA1 are not known to cause autosomal dominant forms of nemaline myopathy (PMID: 12921789, 19562689). Although donor and acceptor splice site variants are typically truncating (PMID: 16199547) and truncating variants in ACTA1 are known to be pathogenic (PMID: 19562689), the pathogenicity of this donor splice site variant in the last intron is not conclusive due to the uncertain impact on mRNA splicing and protein function. Without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 28, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 16199547, 12921789, 25525159, 31589614, 19562689) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at