rs147391618
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_020320.5(RARS2):c.35A>G(p.Gln12Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,613,322 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. 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. Q12E) has been classified as Uncertain significance.
Frequency
Consequence
NM_020320.5 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RARS2 | NM_020320.5 | c.35A>G | p.Gln12Arg | missense_variant, splice_region_variant | 1/20 | ENST00000369536.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RARS2 | ENST00000369536.10 | c.35A>G | p.Gln12Arg | missense_variant, splice_region_variant | 1/20 | 1 | NM_020320.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000679 AC: 17AN: 250478Hom.: 0 AF XY: 0.0000590 AC XY: 8AN XY: 135660
GnomAD4 exome AF: 0.000153 AC: 224AN: 1461162Hom.: 0 Cov.: 33 AF XY: 0.000143 AC XY: 104AN XY: 726766
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74346
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 23, 2023 | Published functional studies found this variant results in abnormal splicing (Rankin J et al., 2010; Cassandrini D et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 30006346, 34426522, 22086604, 27061686, 22569581, 23427196, 20635367, 20952379, 34717047, 35468344, 33972171) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 12 of the RARS2 protein (p.Gln12Arg). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs147391618, gnomAD 0.02%). This missense change has been observed in individuals with pontocerebellar hypoplasia (PMID: 20635367, 20952379, 22569581). ClinVar contains an entry for this variant (Variation ID: 30912). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Studies have shown that this missense change results in alternative splicing and introduces a premature termination codon (PMID: 20635367, 22569581). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jan 10, 2021 | PS3, PM3, PM2 - |
Pontocerebellar hypoplasia type 6 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Aug 28, 2019 | A heterozygous splice site variant was identified, NM_020320.4(RARS2):c.35A>G in exon 1 of 20 of the RARS2 gene (NB: This variant is non-coding in alternative transcripts). RNA analysis shows the variant causes abnormal splicing leading to a frameshift and premature termination codon, NP_064716.2(RARS2):p.(Gln12Argfs*25) (Cassandrini, D. et al. (2013); Rankin, J. et al . (2010)). The variant is predicted to result in loss of normal protein function through nonsense-mediated decay. The variant is present in the gnomAD population database at a frequency of 0.02% (17 heterozygotes, 0 homozygotes) in the non-Finnish European population. It is not present in other subpopulations in gnomAD. It has been previously reported in patients with pontocerebellar hypoplasia type 6 (Cassandrini, D. et al . (2013); Rankin, J. et al. (2010)). In addition, functional studies show RARS2 enzyme activity was severely reduced in the cultured skin fibroblasts of a compound heterozygous patient (Cassandrini, D. et al. (2013)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 20, 2023 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 13, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at