rs1801267
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000110.4(DPYD):c.2657G>A(p.Arg886His) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,612,928 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_000110.4 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: 0.0000329 AC: 5AN: 151970Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000439 AC: 11AN: 250320Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135252
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1460840Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 726720
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152088Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74342
ClinVar
Submissions by phenotype
Dihydropyrimidine dehydrogenase deficiency Pathogenic:1Uncertain:2
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not specified Uncertain:1
Variant summary: DPYD c.2657G>A (p.Arg886His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250320 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency (4.4e-05 vs 0.0025), allowing no conclusion about variant significance. c.2657G>A has been reported in the literature in at least one individual with Dihydropyrimidine Dehydrogenase Deficiency, who carried the variant of interest as well as C29R, both in the homozygous state (Vreken_1997, Van Kuilenburg_1999). The variant has also been cited in the literature in panels testing cancer patients for chemotherapy toxicity. These reports do not provide unequivocal conclusions about association of the variant with Dihydropyrimidine Dehydrogenase Deficiency. The variant was reported in an E. Coli based expression system to have 25% residual acitvity, and in a mammalian cell system to have activity similar to wild-type (Vreken_1997, Offer_2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at