rs1553255506
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The ENST00000366684.7(ACTA1):c.146T>G(p.Met49Arg) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M49V) 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 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACTA1 | NM_001100.4 | c.146T>G | p.Met49Arg | missense_variant | 3/7 | ENST00000366684.7 | NP_001091.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACTA1 | ENST00000366684.7 | c.146T>G | p.Met49Arg | missense_variant | 3/7 | 1 | NM_001100.4 | ENSP00000355645 | P1 | |
ACTA1 | ENST00000366683.4 | c.146T>G | p.Met49Arg | missense_variant | 3/7 | 5 | ENSP00000355644 | |||
ACTA1 | ENST00000684723.1 | c.11T>G | p.Met4Arg | missense_variant | 2/6 | ENSP00000508084 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 38
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Actin accumulation myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 27, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met49 amino acid residue in ACTA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19562689, 20303757). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 532772). This missense change has been observed in individual(s) with clinical features of ACTA1-related conditions (Invitae). 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 methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 49 of the ACTA1 protein (p.Met49Arg). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at