chr22-50525778-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_001953.5(TYMP):c.1441C>T(p.Gln481*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000238 in 1,610,684 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_001953.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152254Hom.: 0 Cov.: 35
GnomAD3 exomes AF: 0.0000559 AC: 13AN: 232468Hom.: 0 AF XY: 0.0000543 AC XY: 7AN XY: 128904
GnomAD4 exome AF: 0.000253 AC: 369AN: 1458430Hom.: 0 Cov.: 39 AF XY: 0.000254 AC XY: 184AN XY: 725524
GnomAD4 genome AF: 0.0000920 AC: 14AN: 152254Hom.: 0 Cov.: 35 AF XY: 0.0000941 AC XY: 7AN XY: 74386
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: TYMP c.1441C>T (p.Gln481X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, however, nonsense mediated decay is not expected to occur. The variant allele was found at a frequency of 5.6e-05 in 232468 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TYMP causing Mitochondrial DNA Depletion Syndrome 1 (MNGIE type) (5.6e-05 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1441C>T in individuals affected with Mitochondrial DNA Depletion Syndrome 1 (MNGIE type) and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 553052). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Mitochondrial DNA depletion syndrome 1 Uncertain:1
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not provided Uncertain:1
This sequence change creates a premature translational stop signal (p.Gln481*) in the TYMP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2 amino acid(s) of the TYMP protein. This variant is present in population databases (rs200735968, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TYMP-related conditions. ClinVar contains an entry for this variant (Variation ID: 553052). 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. -
TYMP-related disorder Uncertain:1
The TYMP c.1441C>T variant is predicted to result in premature protein termination (p.Gln481*). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-50964207-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at