chr1-229432608-C-T
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_001100.4(ACTA1):c.402G>A(p.Met134Ile) 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. M134V) has been classified as Pathogenic.
Frequency
Consequence
NM_001100.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACTA1 | NM_001100.4 | c.402G>A | p.Met134Ile | 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.402G>A | p.Met134Ile | missense_variant | 3/7 | 1 | NM_001100.4 | ENSP00000355645 | P1 | |
ACTA1 | ENST00000366683.4 | c.402G>A | p.Met134Ile | missense_variant | 3/7 | 5 | ENSP00000355644 | |||
ACTA1 | ENST00000684723.1 | c.267G>A | p.Met89Ile | missense_variant | 2/6 | ENSP00000508084 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 38
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Actin accumulation myopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 28, 2017 | This variant has been reported in an individual affected with typical nemaline myopathy (PMID: 19562689). This variant has been seen to segregate with nemaline rod myopathy in a single family (Invitae). In summary, this variant is a rare missense change that has been observed in an affected individual and segregates in a single family with ACTA1 related conditions. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. A different missense substitution at this codon (p.Met134Val, also known as p.Met132Val) has been determined to be likely pathogenic (PMID: 19562689, 10508519, 15226407, 14733965). This suggests that the methionine residue is critical for ACTA1 protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 134 of the ACTA1 protein (p.Met134Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at