chr1-97515865-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

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

Scores

Clinical Significance

drug response reviewed by expert panel U:1B:8O:3

Conservation

PhyloP100: 5.71

Publications

115 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0098076165).

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 26 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000110.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYD	NM_000110.4	MANE Select	c.1601G>A	p.Ser534Asn	missense	Exon 13 of 23	NP_000101.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DPYD	ENST00000370192.8	TSL:1 MANE Select	c.1601G>A	p.Ser534Asn	missense	Exon 13 of 23	ENSP00000359211.3
DPYD	ENST00000876340.1		c.1769G>A	p.Ser590Asn	missense	Exon 14 of 24	ENSP00000546399.1
DPYD	ENST00000969915.1		c.1601G>A	p.Ser534Asn	missense	Exon 13 of 24	ENSP00000639974.1

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

GnomAD2 exomes

AF:

0.0147

AC:

3683

AN:

250562

AF XY:

0.0147

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 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

African (AFR)

AF:

0.00320

AC:

107

AN:

33428

American (AMR)

AF:

0.0120

AC:

536

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.0316

AC:

824

AN:

26082

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39684

South Asian (SAS)

AF:

0.00867

AC:

748

AN:

86240

European-Finnish (FIN)

AF:

0.0139

AC:

742

AN:

53384

Middle Eastern (MID)

AF:

0.0330

AC:

190

AN:

5762

European-Non Finnish (NFE)

AF:

0.0215

AC:

23872

AN:

1111298

Other (OTH)

AF:

0.0196

AC:

1183

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1578

3156

4734

6312

7890

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

910

1820

2730

3640

4550

<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:

0.0137

AC:

2086

AN:

152056

Hom.:

Cov.:

AF XY:

0.0136

AC XY:

1012

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.00395

AC:

164

AN:

41552

American (AMR)

AF:

0.0152

AC:

232

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.0331

AC:

115

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5144

South Asian (SAS)

AF:

0.00726

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0152

AC:

161

AN:

10610

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0196

AC:

1330

AN:

67912

Other (OTH)

AF:

0.0171

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

108

215

323

430

538

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0186

Hom.:

109

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

ClinVar submissions as Germline

Significance:drug response

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dihydropyrimidine dehydrogenase deficiency (4)

not provided (4)

DPYD-related disorder (1)

not specified (1)

capecitabine response - Toxicity (1)

fluorouracil response - Toxicity (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

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

PhyloP100

5.7

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

Mutation Taster

=75/25

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over