chr1-97515839-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000110.4(DPYD):c.1627A>G(p.Ile543Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,612,714 control chromosomes in the GnomAD database, including 31,976 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.19 ( 2802 hom., cov: 32)

Exomes 𝑓: 0.20 ( 29174 hom. )

Consequence

DPYD
NM_000110.4 missense

Scores

Clinical Significance

drug response reviewed by expert panel B:8O:3

Conservation

PhyloP100: 1.40

Publications

176 publications found

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 Gene-Disease associations (from GenCC):

dihydropyrimidine dehydrogenase deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

DPYD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00896588).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYD	NM_000110.4 link	c.1627A>G	p.Ile543Val	missense_variant	Exon 13 of 23	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8 link	c.1627A>G	p.Ile543Val	missense_variant	Exon 13 of 23	1	NM_000110.4	ENSP00000359211.3

Frequencies

GnomAD3 genomes

AF:

0.186

AC:

28219

AN:

151788

Hom.:

2791

Cov.:

show subpopulations

Gnomad AFR

AF:

0.158

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.237

Gnomad ASJ

AF:

0.194

Gnomad EAS

AF:

0.255

Gnomad SAS

AF:

0.0961

Gnomad FIN

AF:

0.167

Gnomad MID

AF:

0.156

Gnomad NFE

AF:

0.196

Gnomad OTH

AF:

0.184

GnomAD2 exomes

AF:

0.198

AC:

49519

AN:

250532

AF XY:

0.189

show subpopulations

Gnomad AFR exome

AF:

0.158

Gnomad AMR exome

AF:

0.297

Gnomad ASJ exome

AF:

0.204

Gnomad EAS exome

AF:

0.254

Gnomad FIN exome

AF:

0.168

Gnomad NFE exome

AF:

0.197

Gnomad OTH exome

AF:

0.197

GnomAD4 exome

AF:

0.196

AC:

285727

AN:

1460808

Hom.:

29174

Cov.:

AF XY:

0.192

AC XY:

139533

AN XY:

726730

show subpopulations

African (AFR)

AF:

0.154

AC:

5160

AN:

33432

American (AMR)

AF:

0.294

AC:

13109

AN:

44600

Ashkenazi Jewish (ASJ)

AF:

0.195

AC:

5084

AN:

26088

East Asian (EAS)

AF:

0.271

AC:

10765

AN:

39684

South Asian (SAS)

AF:

0.0957

AC:

8249

AN:

86240

European-Finnish (FIN)

AF:

0.168

AC:

8951

AN:

53374

Middle Eastern (MID)

AF:

0.150

AC:

865

AN:

5762

European-Non Finnish (NFE)

AF:

0.200

AC:

221968

AN:

1111316

Other (OTH)

AF:

0.192

AC:

11576

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

13613

27226

40839

54452

68065

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7832

15664

23496

31328

39160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.186

AC:

28273

AN:

151906

Hom.:

2802

Cov.:

AF XY:

0.183

AC XY:

13615

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.159

AC:

6583

AN:

41482

American (AMR)

AF:

0.237

AC:

3610

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.194

AC:

673

AN:

3464

East Asian (EAS)

AF:

0.255

AC:

1308

AN:

5132

South Asian (SAS)

AF:

0.0964

AC:

465

AN:

4826

European-Finnish (FIN)

AF:

0.167

AC:

1770

AN:

10598

Middle Eastern (MID)

AF:

0.147

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.196

AC:

13301

AN:

67882

Other (OTH)

AF:

0.189

AC:

399

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1169

2339

3508

4678

5847

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

304

608

912

1216

1520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.197

Hom.:

13873

Bravo

AF:

0.195

TwinsUK

AF:

0.202

AC:

750

ALSPAC

AF:

0.204

AC:

786

ESP6500AA

AF:

0.155

AC:

684

ESP6500EA

AF:

0.198

AC:

1704

ExAC

AF:

0.192

AC:

23357

Asia WGS

AF:

0.192

AC:

669

AN:

3478

EpiCase

AF:

0.198

EpiControl

AF:

0.200

ClinVar

Significance: drug response

Submissions summary: Benign:8Other:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency

Benign:4

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:2Other:1

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DPYD: BP4, BS1, BS2

Diasio Lab, Mayo Clinic

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Feb 23, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DPYD-related disorder

Benign:1

Mar 05, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

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

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

9.5

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.16

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.92

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0090

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.49

PhyloP100

1.4

PrimateAI

Benign

0.31

PROVEAN

Benign

0.73

REVEL

Benign

0.12

Sift

Benign

0.11

Sift4G

Benign

0.14

Vest4

0.036

ClinPred

0.0048

GERP RS

-3.1

Varity_R

0.029

gMVP

0.43

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over