rs781417096
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_020320.5(RARS2):βc.1612delAβ(p.Thr538HisfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000558 in 1,613,402 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Consequence
NM_020320.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251372Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135844
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461212Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4AN XY: 726978
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74350
ClinVar
Submissions by phenotype
Pontocerebellar hypoplasia type 6 Pathogenic:2
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Compound heterozygous pathogenic variants, c.1612delA (p.T538fs) and c.419T>G (p.F140C), in the RARS2 gene were detected in this individual. The c.1612delA change predicts a translation reading frameshift at amino acid 538 (p.T538fs) with subsequent premature translation termination and therefore is classified as pathogenic. The c.419T>G (p.F140C) variant has been previously reported as disease causing [PMID 26795593, 25356970]. Whole exome sequencing and Sanger sequencing also showed that the mother is heterozygous for c.1612delA (p.T538fs) and the father is heterozygous for c.419T>G (p.F140C). Whole exome sequencing and Sanger sequencing also showed the affected sibling is heterozygous for both changes in RARS2. Our data indicate that the two changes in the RARS2 gene are in trans configuration (compound heterozygous) in this patient and the affected sibling. -
not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Thr538Hisfs*4) in the RARS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the RARS2 protein. This variant is present in population databases (rs781417096, gnomAD 0.004%). 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: 522857). This variant disrupts a region of the RARS2 protein in which other variant(s) (p.Arg560His) have been determined to be pathogenic (PMID: 31618753, 31665838, 35068129; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at