chr1-97515865-C-T

Position:

chr1-97515865-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_StrongBS1BS2

The ENST00000370192.8(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
ENST00000370192.8 missense

Scores

Clinical Significance

drug response reviewed by expert panel U:1B:7O:3

Conservation

PhyloP100: 5.71

Variant links:

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]

DPYD links:

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=3, Uncertain_significance=1, Likely_benign=2, drug_response=2, not_provided=1}. 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 GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYD	NM_000110.4 linkuse as main transcript	c.1601G>A	p.Ser534Asn	missense_variant	13/23	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8 linkuse as main transcript	c.1601G>A	p.Ser534Asn	missense_variant	13/23	1	NM_000110.4	ENSP00000359211	P1	Q12882-1

Frequencies

GnomAD3 genomes

AF:

0.0137

AC:

2084

AN:

151938

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00396

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0152

Gnomad ASJ

AF:

0.0331

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00705

Gnomad FIN

AF:

0.0152

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0196

Gnomad OTH

AF:

0.0173

GnomAD3 exomes

AF:

0.0147

AC:

3683

AN:

250562

Hom.:

AF XY:

0.0147

AC XY:

1985

AN XY:

135402

show subpopulations

Gnomad AFR exome

AF:

0.00382

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0302

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00863

Gnomad FIN exome

AF:

0.0135

Gnomad NFE exome

AF:

0.0201

Gnomad OTH exome

AF:

0.0175

GnomAD4 exome

AF:

0.0193

AC:

28204

AN:

1460800

Hom.:

311

Cov.:

AF XY:

0.0189

AC XY:

13709

AN XY:

726732

show subpopulations

Gnomad4 AFR exome

AF:

0.00320

Gnomad4 AMR exome

AF:

0.0120

Gnomad4 ASJ exome

AF:

0.0316

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00867

Gnomad4 FIN exome

AF:

0.0139

Gnomad4 NFE exome

AF:

0.0215

Gnomad4 OTH exome

AF:

0.0196

GnomAD4 genome

AF:

0.0137

AC:

2086

AN:

152056

Hom.:

Cov.:

AF XY:

0.0136

AC XY:

1012

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00395

Gnomad4 AMR

AF:

0.0152

Gnomad4 ASJ

AF:

0.0331

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00726

Gnomad4 FIN

AF:

0.0152

Gnomad4 NFE

AF:

0.0196

Gnomad4 OTH

AF:

0.0171

Alfa

AF:

0.0197

Hom.:

Bravo

AF:

0.0133

TwinsUK

AF:

0.0216

AC:

ALSPAC

AF:

0.0202

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0202

AC:

174

ExAC

AF:

0.0141

AC:

1712

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0246

EpiControl

AF:

0.0240

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

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. -
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 -

Dihydropyrimidine dehydrogenase deficiency

Uncertain:1Benign:2

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	- -
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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 29, 2016

- -

DPYD-related disorder

Benign:1

Benign, no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.42

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0098

MetaSVM

Uncertain

0.31

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.43

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.014

Polyphen

1.0

Vest4

0.26

MPC

0.055

ClinPred

0.032

GERP RS

5.2

Varity_R

0.48

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over