rs587777589
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_020745.4(AARS2):βc.647_648insGβ(p.Cys218LeufsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000917 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000053 ( 0 hom., cov: 33)
Exomes π: 0.000096 ( 0 hom. )
Consequence
AARS2
NM_020745.4 frameshift
NM_020745.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.91
Genes affected
AARS2 (HGNC:21022): (alanyl-tRNA synthetase 2, mitochondrial) The protein encoded by this gene belongs to the class-II aminoacyl-tRNA synthetase family. Aminoacyl-tRNA synthetases play critical roles in mRNA translation by charging tRNAs with their cognate amino acids. The encoded protein is a mitochondrial enzyme that specifically aminoacylates alanyl-tRNA. Mutations in this gene are a cause of combined oxidative phosphorylation deficiency 8. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 6-44311095-G-GC is Pathogenic according to our data. Variant chr6-44311095-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 143044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AARS2 | NM_020745.4 | c.647_648insG | p.Cys218LeufsTer6 | frameshift_variant | 4/22 | ENST00000244571.5 | |
LOC124901322 | XR_007059594.1 | n.301-3054dup | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AARS2 | ENST00000244571.5 | c.647_648insG | p.Cys218LeufsTer6 | frameshift_variant | 4/22 | 1 | NM_020745.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152174Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000717 AC: 18AN: 251070Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135826
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GnomAD4 exome AF: 0.0000958 AC: 140AN: 1461788Hom.: 0 Cov.: 32 AF XY: 0.0000935 AC XY: 68AN XY: 727180
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Combined oxidative phosphorylation defect type 8 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 17, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 02, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with combined oxidative phosphorylation deficiency 8 (MIM#614096) and leukoencephalopathy, progressive, with ovarian failure (MIM#615889) (PMIDs: 28633377, 30285085, 24808023). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (20 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. At least nine NMD-predicted variants along AARS2 have been reported in affected individuals (ClinVar, Decipher, PMID: 31106991). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in individuals diagnosed with severe infantile cardiomyopathy, progressive leukoencephalopathy with ovarian failure and primary pulmonary hypoplasia (ClinVar; PMIDs: 25058219, 29971983, 30819764). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_020745.4:c.1774C>T; p.(Arg592Trp)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Heidelberg University | Dec 16, 2022 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 143044). This variant is also known as c.647_648insG. This premature translational stop signal has been observed in individual(s) with multiple respiratory chain complex defects (PMID: 25058219). This variant is present in population databases (rs746514660, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Cys218Leufs*6) in the AARS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AARS2 are known to be pathogenic (PMID: 24808023, 30285085, 30819764). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 29, 2019 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29971983, 30819764, 25058219) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 08, 2016 | - - |
Pulmonary hypoplasia Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Pediatric Genomics Discovery Program, Yale University | Feb 05, 2019 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at