rs121909523
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_001100.4(ACTA1):c.782A>T(p.Glu261Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,459,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000069 ( 0 hom. )
Consequence
ACTA1
NM_001100.4 missense
NM_001100.4 missense
Scores
13
4
1
Clinical Significance
Conservation
PhyloP100: 6.17
Genes affected
ACTA1 (HGNC:129): (actin alpha 1, skeletal muscle) The product encoded by this gene belongs to the actin family of proteins, which are highly conserved proteins that play a role in cell motility, structure and integrity. Alpha, beta and gamma actin isoforms have been identified, with alpha actins being a major constituent of the contractile apparatus, while beta and gamma actins are involved in the regulation of cell motility. This actin is an alpha actin that is found in skeletal muscle. Mutations in this gene cause a variety of myopathies, including nemaline myopathy, congenital myopathy with excess of thin myofilaments, congenital myopathy with cores, and congenital myopathy with fiber-type disproportion, diseases that lead to muscle fiber defects with manifestations such as hypotonia. [provided by RefSeq, Sep 2019]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
?
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001100.4
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, ACTA1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
?
Variant 1-229432020-T-A is Pathogenic according to our data. Variant chr1-229432020-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-229432020-T-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTA1 | NM_001100.4 | c.782A>T | p.Glu261Val | missense_variant | 5/7 | ENST00000366684.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTA1 | ENST00000366684.7 | c.782A>T | p.Glu261Val | missense_variant | 5/7 | 1 | NM_001100.4 | P1 | |
ACTA1 | ENST00000366683.4 | c.782A>T | p.Glu261Val | missense_variant | 5/7 | 5 | |||
ACTA1 | ENST00000684723.1 | c.647A>T | p.Glu216Val | missense_variant | 4/6 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome AF: 0.00000685 AC: 10AN: 1459368Hom.: 0 Cov.: 34 AF XY: 0.00000689 AC XY: 5AN XY: 725922
GnomAD4 exome
AF:
AC:
10
AN:
1459368
Hom.:
Cov.:
34
AF XY:
AC XY:
5
AN XY:
725922
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 31, 2023 | Published functional studies demonstrate a damaging effect: abnormal protein folding (PMID: 15226407); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10508519, 26582918, 27535533, 24077912, 15226407) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Dec 30, 2020 | PS3, PM2 - |
Actin accumulation myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 08, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ACTA1 function (PMID: 15226407). 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: 18283). This variant is also known as p.Glu259Val. This missense change has been observed in individual(s) with autosomal recessive nemaline myopathy (PMID: 10508519, 15236405). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121909523, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 261 of the ACTA1 protein (p.Glu261Val). - |
Congenital myopathy with fiber type disproportion;C3711389:Actin accumulation myopathy;C4225181:Progressive scapulohumeroperoneal distal myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 14, 2021 | - - |
Congenital myopathy 2b, severe infantile, autosomal recessive Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1999 | - - |
ACTA1-related myopathies Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 08, 2019 | The ACTA1 c.782A>T (p.Glu261Val) variant, also referred to as p.Glu259Val, is a missense variant that has been reported in two studies which describe three compound heterozygous individuals with severe, autosomal recessive, nemaline myopathy, including a pair of siblings (Nowak et al. 1999; Agrawal et al. 2004). In both studies, the p.Glu261Val variant was inherited from heterozygous, clinically-unaffected parents. The p.Glu261Val variant was absent from 100 control subjects and is reported at a frequency of 0.000065 in the European (Non-Finnish) population of the Genome Aggregation Database though this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Costa et al. (2004) evaluated the effect of the variant on protein folding and found that the variant protein was not released from prefoldin and CCT nor did it associated with actin-monomer-binding proteins, indicating a defective protein. Based on rarity of the variant, its identification in multiple affected individuals in the literature, and its effect on protein function, the p.Glu261Val variant is classified as likely pathogenic for ACTA1-related myopathies. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at E261 (P = 0.2322);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at