rs749708983
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_005051.3(QARS1):c.117+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000005 in 1,599,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_005051.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
QARS1 | NM_005051.3 | c.117+4C>T | splice_region_variant, intron_variant | Intron 1 of 23 | ENST00000306125.12 | NP_005042.1 | ||
QARS1 | NM_001272073.2 | c.117+4C>T | splice_region_variant, intron_variant | Intron 1 of 23 | NP_001259002.1 | |||
QARS1 | XM_017006965.3 | c.117+4C>T | splice_region_variant, intron_variant | Intron 1 of 22 | XP_016862454.2 | |||
QARS1 | NR_073590.2 | n.141+4C>T | splice_region_variant, intron_variant | Intron 1 of 23 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152244Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000123 AC: 3AN: 244552Hom.: 0 AF XY: 0.00000750 AC XY: 1AN XY: 133288
GnomAD4 exome AF: 0.00000346 AC: 5AN: 1447078Hom.: 0 Cov.: 32 AF XY: 0.00000279 AC XY: 2AN XY: 716892
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74382
ClinVar
Submissions by phenotype
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge -
Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome Uncertain:1
This sequence change falls in intron 1 of the QARS gene. It does not directly change the encoded amino acid sequence of the QARS protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs749708983, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with QARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 240089). Variants that disrupt 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 create or strengthen a splice site. 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. -
QARS1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at