6-87530801-A-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_020320.5(RARS2):c.754T>A(p.Tyr252Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000283 in 1,614,016 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 Uncertain significance (★★).
Frequency
Consequence
NM_020320.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000207 AC: 52AN: 251476Hom.: 0 AF XY: 0.000250 AC XY: 34AN XY: 135910
GnomAD4 exome AF: 0.000296 AC: 432AN: 1461852Hom.: 0 Cov.: 31 AF XY: 0.000315 AC XY: 229AN XY: 727232
GnomAD4 genome AF: 0.000164 AC: 25AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74338
ClinVar
Submissions by phenotype
not provided Uncertain:4
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In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 252 of the RARS2 protein (p.Tyr252Asn). This variant is present in population databases (rs140692271, gnomAD 0.1%). 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: 358236). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
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Pontocerebellar hypoplasia type 6 Uncertain:2
A heterozygous missense variant was identified, NM_020320.4(RARS2):c.754T>A in exon 9 of 20 of the RARS2 gene. This substitution is predicted to create a major amino acid change from tyrosine to asparagine at position 252 of the protein, NP_064716.2(RARS2):p.(Tyr252Asn). The tyrosine at this position has very high conservation (100 vertebrates, UCSC), and is located within the tRNA synthetases class I (R) domain. In silico software predicts this variant to be pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at frequencies of 0.03% (38 heterozygotes, 0 homozygotes) in the non-Finnish European population and 0.02% (59 heterozygotes, 0 homozygotes) in the global population. It has been previously reported as a variant of uncertain significance (VUS) in clinical cases (ClinVar). Based on information available at the time of curation, this variant has been classified as a VUS with POTENTIAL CLINICAL RELEVANCE. -
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not specified Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at