1-97515865-C-T
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_StrongBS1BS2
The NM_000110.4(DPYD):c.1601G>A(p.Ser534Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0188 in 1,612,856 control chromosomes in the GnomAD database, including 337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Synonymous variant affecting the same amino acid position (i.e. S534S) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.014 ( 26 hom., cov: 32)
Exomes 𝑓: 0.019 ( 311 hom. )
Consequence
DPYD
NM_000110.4 missense
NM_000110.4 missense
Scores
1
11
6
Clinical Significance
Conservation
PhyloP100: 5.71
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -16 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0098076165).
BP6
?
Variant 1-97515865-C-T is Benign according to our data. Variant chr1-97515865-C-T is described in ClinVar as [drug_response]. Clinvar id is 100094.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=2, Uncertain_significance=1, not_provided=1, drug_response=2}. Variant chr1-97515865-C-T is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0137 (2086/152056) while in subpopulation NFE AF= 0.0196 (1330/67912). AF 95% confidence interval is 0.0187. There are 26 homozygotes in gnomad4. There are 1012 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd at 26 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DPYD | NM_000110.4 | c.1601G>A | p.Ser534Asn | missense_variant | 13/23 | ENST00000370192.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DPYD | ENST00000370192.8 | c.1601G>A | p.Ser534Asn | missense_variant | 13/23 | 1 | NM_000110.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0137 AC: 2084AN: 151938Hom.: 26 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
2084
AN:
151938
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0147 AC: 3683AN: 250562Hom.: 40 AF XY: 0.0147 AC XY: 1985AN XY: 135402
GnomAD3 exomes
AF:
AC:
3683
AN:
250562
Hom.:
AF XY:
AC XY:
1985
AN XY:
135402
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0193 AC: 28204AN: 1460800Hom.: 311 Cov.: 33 AF XY: 0.0189 AC XY: 13709AN XY: 726732
GnomAD4 exome
AF:
AC:
28204
AN:
1460800
Hom.:
Cov.:
33
AF XY:
AC XY:
13709
AN XY:
726732
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0137 AC: 2086AN: 152056Hom.: 26 Cov.: 32 AF XY: 0.0136 AC XY: 1012AN XY: 74312
GnomAD4 genome
?
AF:
AC:
2086
AN:
152056
Hom.:
Cov.:
32
AF XY:
AC XY:
1012
AN XY:
74312
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
80
ALSPAC
AF:
AC:
78
ESP6500AA
AF:
AC:
20
ESP6500EA
AF:
AC:
174
ExAC
?
AF:
AC:
1712
Asia WGS
AF:
AC:
18
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: drug response
Submissions summary: Uncertain:1Benign:7Other:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Benign:3Other:1
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 08, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | DPYD: BS1, BS2 - |
not provided, no classification provided | literature only | Diasio Lab, Mayo Clinic | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 26, 2018 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Dihydropyrimidine dehydrogenase deficiency Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Aug 03, 2015 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 29, 2016 | - - |
DPYD-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 21, 2024 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
fluorouracil response - Toxicity Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity |
capecitabine response - Toxicity Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at