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

Genomes: not found (cov: 31)

Consequence

ACTA1
NM_001100.4 missense

Scores

8
5
5

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.87
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-229432610-T-C is described in Lovd as [Pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTA1. . Gene score misZ 4.5292 (greater than the threshold 3.09). Trascript score misZ 6.088 (greater than threshold 3.09). GenCC has associacion of gene with congenital myopathy with excess of thin filaments, nemaline myopathy 3, intermediate nemaline myopathy, typical nemaline myopathy, congenital fiber-type disproportion myopathy, severe congenital nemaline myopathy, rigid spine syndrome, zebra body myopathy, childhood-onset nemaline myopathy, congenital myopathy 2c, severe infantile, autosomal dominant, alpha-actinopathy, progressive scapulohumeroperoneal distal myopathy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.937
PP5
Variant 1-229432608-C-T is Pathogenic according to our data. Variant chr1-229432608-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 464122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-229432608-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ACTA1NM_001100.4 linkuse as main transcriptc.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
ACTA1ENST00000366684.7 linkuse as main transcriptc.402G>A p.Met134Ile missense_variant 3/71 NM_001100.4 ENSP00000355645 P1
ACTA1ENST00000366683.4 linkuse as main transcriptc.402G>A p.Met134Ile missense_variant 3/75 ENSP00000355644
ACTA1ENST00000684723.1 linkuse as main transcriptc.267G>A p.Met89Ile missense_variant 2/6 ENSP00000508084

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
38
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Actin accumulation myopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 28, 2017This 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 submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.89
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.86
D;D
Eigen
Benign
0.17
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Pathogenic
0.68
D
MetaRNN
Pathogenic
0.94
D;D
MetaSVM
Uncertain
0.73
D
MutationAssessor
Benign
1.7
L;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-2.0
N;.
REVEL
Pathogenic
0.82
Sift4G
Benign
0.078
T;T
Polyphen
0.0040
B;.
Vest4
0.95
MutPred
0.72
Loss of catalytic residue at I138 (P = 0.2248);Loss of catalytic residue at I138 (P = 0.2248);
MVP
0.99
ClinPred
0.97
D
GERP RS
4.5
Varity_R
0.92
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553255486; hg19: chr1-229568355; API