rs1553255521
Variant summary
Our verdict is Pathogenic. Variant got 27 ACMG points: 27P and 0B. PS1_Very_StrongPM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001100.4(ACTA1):c.109G>T(p.Val37Leu) 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 Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V37A) has been classified as Pathogenic.
Frequency
Consequence
NM_001100.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 27 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTA1 | NM_001100.4 | c.109G>T | p.Val37Leu | missense_variant | 2/7 | ENST00000366684.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTA1 | ENST00000366684.7 | c.109G>T | p.Val37Leu | missense_variant | 2/7 | 1 | NM_001100.4 | P1 | |
ACTA1 | ENST00000366683.4 | c.109G>T | p.Val37Leu | missense_variant | 2/7 | 5 | |||
ACTA1 | ENST00000684723.1 | c.-6-127G>T | intron_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 38
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Actin accumulation myopathy Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 27, 2017 | This variant has been reported in an individual affected with nemaline myopathy (PMID: 19562689, 23394784). In summary, this variant is a rare missense change that has been reported in multiple affected individuals. For these reasons, it has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). A different nucleotide change (c.109G>C) that produces the same amino acid change as this variant (p.Val37Leu) has been reported in multiple individuals affected with nemaline myopathy (PMID: 19562689, 12921789, 15236405). In 2 of these cases this variant was reported to arise de novo (PMID: 19562689, 12921789, 15236405). The c.109G>C sequence change has also been reported as p.Val35Leu. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 37 of the ACTA1 protein (p.Val37Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This mutation has been previously described as disease-causing in the literature, as has another mutation causing the same amino acid substitution. It has been identified once in our laboratory as a de novo mutation in a 1-month-old female with nemaline myopathy, hypotonia, respiratory distress, and cardiac arrest - |
Pathogenic, criteria provided, single submitter | provider interpretation | Pediatric Department, Peking University First Hospital | Apr 11, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at