1-229432408-C-T
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The ENST00000366684.7(ACTA1):c.478G>A(p.Gly160Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G160C) has been classified as Pathogenic.
Frequency
Consequence
ENST00000366684.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACTA1 | NM_001100.4 | c.478G>A | p.Gly160Ser | missense_variant | 4/7 | ENST00000366684.7 | NP_001091.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACTA1 | ENST00000366684.7 | c.478G>A | p.Gly160Ser | missense_variant | 4/7 | 1 | NM_001100.4 | ENSP00000355645 | P1 | |
ACTA1 | ENST00000366683.4 | c.478G>A | p.Gly160Ser | missense_variant | 4/7 | 5 | ENSP00000355644 | |||
ACTA1 | ENST00000684723.1 | c.343G>A | p.Gly115Ser | missense_variant | 3/6 | ENSP00000508084 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Actin accumulation myopathy Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 05, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly160 amino acid residue in ACTA1. Other variant(s) that disrupt this residue have been observed in individuals with ACTA1-related conditions (PMID: 19562689), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACTA1 protein function. ClinVar contains an entry for this variant (Variation ID: 420707). This missense change has been observed in individual(s) with autosomal dominant ACTA1-related conditions (PMID: 25326635, 31724238). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 160 of the ACTA1 protein (p.Gly160Ser). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2016 | The G160S variant in the ACTA1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, a missense pathogenic variant at this same codon (G160C), as well as missense pathogenic variants in neighboring codons (D156N, H163D, V165L, V165M), have been reported in the Human Gene Mutation Database in association with ACTA1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The G160S variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G160S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The G160S variant is a strong candidate for a pathogenic variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at