rs121909531
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_001100.4(ACTA1):c.1000C>T(p.Pro334Ser) 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. P334L) 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 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTA1 | NM_001100.4 | c.1000C>T | p.Pro334Ser | missense_variant | 7/7 | ENST00000366684.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTA1 | ENST00000366684.7 | c.1000C>T | p.Pro334Ser | missense_variant | 7/7 | 1 | NM_001100.4 | P1 | |
ENST00000702606.1 | n.268G>A | non_coding_transcript_exon_variant | 1/1 | ||||||
ACTA1 | ENST00000684723.1 | c.865C>T | p.Pro289Ser | missense_variant | 6/6 | ||||
ACTA1 | ENST00000366683.4 | c.991-69C>T | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Actin accumulation myopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 06, 2022 | Experimental studies have shown that this missense change affects ACTA1 function (PMID: 19206168). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro334 amino acid residue in ACTA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 18291). This variant is also known as p.Pro332Ser. This missense change has been observed in individual(s) with autosomal dominant congenital fiber type disproportion (PMID: 15468086). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 334 of the ACTA1 protein (p.Pro334Ser). - |
Congenital myopathy 2c, severe infantile, autosomal dominant Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2004 | - - |
Congenital myopathy with fiber type disproportion Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at