rs746991079
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000110.4(DPYD):βc.2579delβ(p.Gln860ArgfsTer9) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000502 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000053 ( 0 hom., cov: 32)
Exomes π: 0.000050 ( 0 hom. )
Consequence
DPYD
NM_000110.4 frameshift
NM_000110.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.70
Genes affected
DPYD (HGNC:3012): (dihydropyrimidine dehydrogenase) The protein encoded by this gene is a pyrimidine catabolic enzyme and the initial and rate-limiting factor in the pathway of uracil and thymidine catabolism. Mutations in this gene result in dihydropyrimidine dehydrogenase deficiency, an error in pyrimidine metabolism associated with thymine-uraciluria and an increased risk of toxicity in cancer patients receiving 5-fluorouracil chemotherapy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-97193111-CT-C is Pathogenic according to our data. Variant chr1-97193111-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DPYD | NM_000110.4 | c.2579del | p.Gln860ArgfsTer9 | frameshift_variant | 20/23 | ENST00000370192.8 | |
DPYD-AS1 | NR_046590.1 | n.65-72302del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DPYD | ENST00000370192.8 | c.2579del | p.Gln860ArgfsTer9 | frameshift_variant | 20/23 | 1 | NM_000110.4 | P1 | |
DPYD-AS1 | ENST00000422980.1 | n.65-72302del | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152230Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251116Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135704
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GnomAD4 exome AF: 0.0000499 AC: 73AN: 1461736Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37AN XY: 727176
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74366
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Dihydropyrimidine dehydrogenase deficiency Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 17, 2022 | Variant summary: DPYD c.2579delA (p.Gln860ArgfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as likely pathogenic by our laboratory. The variant allele was found at a frequency of 3.6e-05 in 251116 control chromosomes. c.2579delA has been reported in the literature in individuals affected with Dihydropyrimidine Dehydrogenase Deficiency (e.g. van Staveren_2011). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 03, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 02, 2024 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 02, 2022 | Reported previously as a pathogenic variant in the heterozygous state in two individuals with DPD deficiency (van Staveren et al., 2011); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21590448, 26551538) - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at