rs121909526
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Moderate
The NM_001100.4(ACTA1):c.414C>G(p.Ile138Met) variant causes a missense change involving the alteration of a non-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. I138N) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001100.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTA1 | NM_001100.4 | c.414C>G | p.Ile138Met | missense_variant | 3/7 | ENST00000366684.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTA1 | ENST00000366684.7 | c.414C>G | p.Ile138Met | missense_variant | 3/7 | 1 | NM_001100.4 | P1 | |
ACTA1 | ENST00000366683.4 | c.414C>G | p.Ile138Met | missense_variant | 3/7 | 5 | |||
ACTA1 | ENST00000684723.1 | c.279C>G | p.Ile93Met | missense_variant | 2/6 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 38
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Actin accumulation myopathy Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 16, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 138 of the ACTA1 protein (p.Ile138Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant nemaline myopathy and/or clinical features of autosomal dominant ACTA1-related conditions (PMID: 10838259, 11333380; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as I136M. ClinVar contains an entry for this variant (Variation ID: 18286). 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 not expected to disrupt ACTA1 protein function. Experimental studies have shown that this missense change affects ACTA1 function (PMID: 15226407, 23294764). This variant disrupts the p.Ile138 amino acid residue in ACTA1. Other variant(s) that disrupt this residue have been observed in individuals with ACTA1-related conditions (PMID: 11333380, 19562689), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at