3-49099761-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_005051.3(QARS1):c.1388G>A(p.Arg463Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000041 in 1,461,682 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 Uncertain significance (★).
Frequency
Consequence
NM_005051.3 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250922Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135616
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461682Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3AN XY: 727150
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome Uncertain:1
This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 463 of the QARS protein (p.Arg463Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant also falls at the last nucleotide of exon 15 of the QARS coding sequence, which is part of the consensus splice site for this exon. This variant has not been reported in the literature in individuals with QARS-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at