rs767150990
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong
The NM_020320.5(RARS2):c.1405C>T(p.Arg469Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000347 in 1,612,222 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R469H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_020320.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RARS2 | NM_020320.5 | c.1405C>T | p.Arg469Cys | missense_variant | 16/20 | ENST00000369536.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RARS2 | ENST00000369536.10 | c.1405C>T | p.Arg469Cys | missense_variant | 16/20 | 1 | NM_020320.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152026Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249858Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135140
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1460196Hom.: 0 Cov.: 32 AF XY: 0.0000399 AC XY: 29AN XY: 726592
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152026Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74260
ClinVar
Submissions by phenotype
Pontocerebellar hypoplasia type 6 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Mar 05, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Feb 22, 2019 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 06, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 469 of the RARS2 protein (p.Arg469Cys). This variant is present in population databases (rs767150990, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 548557). 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 RARS2 protein function. This variant disrupts the p.Arg469 amino acid residue in RARS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22569581). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 17, 2023 | Variant summary: RARS2 c.1405C>T (p.Arg469Cys) results in a non-conservative amino acid change located in the DALR anticodon binding (IPR008909) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249858 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1405C>T in individuals affected with Pontocerebellar Hypoplasia, Type 6 and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at