rs141597515
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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):c.208C>T(p.Arg70Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000093 in 1,613,460 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
DPYD
NM_000110.4 stop_gained
NM_000110.4 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 4.36
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
Very rare variant in population databases, with high coverage;
PP5
Variant 1-97828139-G-A is Pathogenic according to our data. Variant chr1-97828139-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370660.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.208C>T | p.Arg70Ter | stop_gained | 3/23 | ENST00000370192.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DPYD | ENST00000370192.8 | c.208C>T | p.Arg70Ter | stop_gained | 3/23 | 1 | NM_000110.4 | P1 | |
DPYD | ENST00000306031.5 | c.208C>T | p.Arg70Ter | stop_gained | 3/6 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152058Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250926Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135618
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461402Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 726992
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152058Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74250
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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:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 27, 2021 | Variant summary: DPYD c.208C>T (p.Arg70X) 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 pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 250926 control chromosomes (gnomAD). To our knowledge, no occurrence of c.208C>T in individuals affected with Dihydropyrimidine Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 05, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 19, 2023 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
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Splicing
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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