rs72549304
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_000110.4(DPYD):c.1475C>T(p.Ser492Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,686 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
DPYD
NM_000110.4 missense
NM_000110.4 missense
Scores
11
6
2
Clinical Significance
Conservation
PhyloP100: 9.53
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.837
PP5
Variant 1-97549609-G-A is Pathogenic according to our data. Variant chr1-97549609-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 298293.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=2, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DPYD | NM_000110.4 | c.1475C>T | p.Ser492Leu | missense_variant | 12/23 | ENST00000370192.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DPYD | ENST00000370192.8 | c.1475C>T | p.Ser492Leu | missense_variant | 12/23 | 1 | NM_000110.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152086Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251052Hom.: 0 AF XY: 0.0000590 AC XY: 8AN XY: 135680
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GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461600Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 727084
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152086Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74270
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Dihydropyrimidine dehydrogenase deficiency Pathogenic:3Uncertain:2
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 04, 2021 | Variant summary: DPYD c.1475C>T (p.Ser492Leu) results in a non-conservative amino acid change located in the FAD/NAD(P)-binding domain (IPR023753) of 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 251052 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.1475C>T has been reported in the literature in a homozygous state in at least one individual affected with pediatric Dihydropyrimidine Dehydrogenase Deficiency (e.g. Van Kuilenburg_2002). The variant has also been reported as heterozygous in at least one individual who exhibited signs of toxicity upon treatment with capecitabine (e.g. Milano_2016, Etienee-Grimaldi_2017). These data indicate that the variant may be associated with disease. Experimental evidence showed that the variant resulted in significantly reduced enzyme activity in both patient cells and when expressed in an isogenic cell line (e.g. Van Kuilenburg_2002, Offer_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The DPYD c.1475C>T (p.Ser492Leu) missense variant has been reported in one study in which it was found in one individual with dihydropyrimidine dehydrogenase deficiency in a homozygous state (van Kuilenburg et al. 2002). Control data are unavailable for this variant, which is reported at a frequency of 0.00048 in the African population of the Exome Aggregation Consortium. Expression studies showed that the variant resulted in a dramatic reduction in the capacity of the variant enzyme to convert 5-FU to dihydrofluorouracil, the product of DPD catabolism, compared to wild type (Offer et al. 2014). Analysis of the crystal structure showed that the serine residue is located in the binding site for the cofactor FAD and therefore the p.Ser492Leu variant is likely to interfere with cofactor binding due to the substitution of the larger leucine residue with a hydrophobic side-chain. The clinical evidence for this variant is limited. The p.Ser492Leu variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for dihydropyrimidine dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 09, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 09, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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