1-97699535-T-C

Position:

chr1-97699535-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_StrongBA1

The NM_000110.4(DPYD):c.496A>G(p.Met166Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0895 in 1,612,978 control chromosomes in the GnomAD database, including 7,345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.080 ( 626 hom., cov: 32)

Exomes 𝑓: 0.090 ( 6719 hom. )

Consequence

DPYD
NM_000110.4 missense

Scores

Clinical Significance

drug response reviewed by expert panel U:1B:5O:3

Conservation

PhyloP100: 7.56

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=0.0019071698).

BP6

Variant 1-97699535-T-C is Benign according to our data. Variant chr1-97699535-T-C is described in ClinVar as [drug_response]. Clinvar id is 100116.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, not_provided=1, Benign=3, drug_response=2, Uncertain_significance=1}. Variant chr1-97699535-T-C is described in Lovd as [Benign]. Variant chr1-97699535-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYD	NM_000110.4 linkuse as main transcript	c.496A>G	p.Met166Val	missense_variant	6/23	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.496A>G	p.Met166Val	missense_variant	6/23	1	NM_000110.4	ENSP00000359211	P1	Q12882-1
DPYD	ENST00000474241.1 linkuse as main transcript	n.260A>G		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes

AF:

0.0801

AC:

12181

AN:

152000

Hom.:

626

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0336

Gnomad AMI

AF:

0.122

Gnomad AMR

AF:

0.0666

Gnomad ASJ

AF:

0.0842

Gnomad EAS

AF:

0.0162

Gnomad SAS

AF:

0.0734

Gnomad FIN

AF:

0.176

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.101

Gnomad OTH

AF:

0.0817

GnomAD3 exomes

AF:

0.0853

AC:

21419

AN:

251038

Hom.:

1135

AF XY:

0.0899

AC XY:

12198

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.0334

Gnomad AMR exome

AF:

0.0359

Gnomad ASJ exome

AF:

0.0775

Gnomad EAS exome

AF:

0.0158

Gnomad SAS exome

AF:

0.0906

Gnomad FIN exome

AF:

0.179

Gnomad NFE exome

AF:

0.100

Gnomad OTH exome

AF:

0.0883

GnomAD4 exome

AF:

0.0905

AC:

132173

AN:

1460860

Hom.:

6719

Cov.:

AF XY:

0.0920

AC XY:

66851

AN XY:

726740

show subpopulations

Gnomad4 AFR exome

AF:

0.0326

Gnomad4 AMR exome

AF:

0.0388

Gnomad4 ASJ exome

AF:

0.0767

Gnomad4 EAS exome

AF:

0.0179

Gnomad4 SAS exome

AF:

0.0900

Gnomad4 FIN exome

AF:

0.171

Gnomad4 NFE exome

AF:

0.0934

Gnomad4 OTH exome

AF:

0.0853

GnomAD4 genome

AF:

0.0802

AC:

12194

AN:

152118

Hom.:

626

Cov.:

AF XY:

0.0833

AC XY:

6196

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0339

Gnomad4 AMR

AF:

0.0665

Gnomad4 ASJ

AF:

0.0842

Gnomad4 EAS

AF:

0.0162

Gnomad4 SAS

AF:

0.0732

Gnomad4 FIN

AF:

0.176

Gnomad4 NFE

AF:

0.101

Gnomad4 OTH

AF:

0.0814

Alfa

AF:

0.0911

Hom.:

1820

Bravo

AF:

0.0690

TwinsUK

AF:

0.0879

AC:

326

ALSPAC

AF:

0.0872

AC:

336

ESP6500AA

AF:

0.0409

AC:

180

ESP6500EA

AF:

0.0991

AC:

852

ExAC

AF:

0.0863

AC:

10475

Asia WGS

AF:

0.0480

AC:

169

AN:

3478

EpiCase

AF:

0.101

EpiControl

AF:

0.0995

ClinVar

Significance: drug response

Submissions summary: Uncertain:1Benign:5Other:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

not provided, no classification provided	literature only	Diasio Lab, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	DPYD: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

Dihydropyrimidine dehydrogenase deficiency

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 29, 2016

- -

DPYD-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 14, 2023

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 29, 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

0.22

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0019

MetaSVM

Uncertain

0.12

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

8.8e-9

P;P

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.52

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.28

MPC

0.36

ClinPred

0.0057

GERP RS

5.3

Varity_R

0.76

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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