dbSNP rs1801160: DPYD:p.Val732Ile (chr1-97305364-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NR_046590.1(DPYD-AS1):n.129-825C>T variant causes a intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0467 in 1,612,218 control chromosomes in the GnomAD database, including 2,145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.040 ( 158 hom., cov: 32)

Exomes 𝑓: 0.047 ( 1987 hom. )

Consequence

DPYD-AS1
NR_046590.1 intron

Scores

Clinical Significance

drug response reviewed by expert panel B:6O:4

Conservation

PhyloP100: 7.50

Publications

156 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 links:

DPYD-AS1 (HGNC:40195): (DPYD antisense RNA 1)

DPYD-AS1 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=0.0043622553).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0859 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NR_046590.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYD	NM_000110.4	MANE Select	c.2194G>A	p.Val732Ile	missense	Exon 18 of 23	NP_000101.2	Q12882-1
	DPYD-AS1	NR_046590.1		n.129-825C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DPYD	ENST00000370192.8	TSL:1 MANE Select	c.2194G>A	p.Val732Ile	missense	Exon 18 of 23	ENSP00000359211.3	Q12882-1
DPYD	ENST00000876340.1		c.2362G>A	p.Val788Ile	missense	Exon 19 of 24	ENSP00000546399.1
DPYD	ENST00000969915.1		c.2194G>A	p.Val732Ile	missense	Exon 18 of 24	ENSP00000639974.1

Frequencies

GnomAD3 genomes

AF:

0.0401

AC:

6089

AN:

151842

Hom.:

158

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0245

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0460

Gnomad ASJ

AF:

0.107

Gnomad EAS

AF:

0.0154

Gnomad SAS

AF:

0.0917

Gnomad FIN

AF:

0.0221

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0452

Gnomad OTH

AF:

0.0604

GnomAD2 exomes

AF:

0.0469

AC:

11760

AN:

250888

AF XY:

0.0513

show subpopulations

Gnomad AFR exome

AF:

0.0243

Gnomad AMR exome

AF:

0.0259

Gnomad ASJ exome

AF:

0.107

Gnomad EAS exome

AF:

0.0194

Gnomad FIN exome

AF:

0.0207

Gnomad NFE exome

AF:

0.0462

Gnomad OTH exome

AF:

0.0606

GnomAD4 exome

AF:

0.0474

AC:

69278

AN:

1460258

Hom.:

1987

Cov.:

AF XY:

0.0494

AC XY:

35900

AN XY:

726484

show subpopulations

African (AFR)

AF:

0.0256

AC:

854

AN:

33378

American (AMR)

AF:

0.0279

AC:

1244

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.108

AC:

2814

AN:

26052

East Asian (EAS)

AF:

0.0190

AC:

755

AN:

39652

South Asian (SAS)

AF:

0.0964

AC:

8317

AN:

86246

European-Finnish (FIN)

AF:

0.0234

AC:

1250

AN:

53394

Middle Eastern (MID)

AF:

0.125

AC:

721

AN:

5750

European-Non Finnish (NFE)

AF:

0.0450

AC:

49981

AN:

1110880

Other (OTH)

AF:

0.0555

AC:

3342

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

3778

7556

11334

15112

18890

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1898

3796

5694

7592

9490

<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:

0.0401

AC:

6090

AN:

151960

Hom.:

158

Cov.:

AF XY:

0.0393

AC XY:

2917

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.0245

AC:

1017

AN:

41518

American (AMR)

AF:

0.0459

AC:

699

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.107

AC:

370

AN:

3464

East Asian (EAS)

AF:

0.0154

AC:

AN:

5132

South Asian (SAS)

AF:

0.0930

AC:

447

AN:

4806

European-Finnish (FIN)

AF:

0.0221

AC:

234

AN:

10600

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0452

AC:

3070

AN:

67902

Other (OTH)

AF:

0.0602

AC:

127

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

295

591

886

1182

1477

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<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:

0.0468

Hom.:

669

Bravo

AF:

0.0407

TwinsUK

AF:

0.0369

AC:

137

ALSPAC

AF:

0.0423

AC:

163

ESP6500AA

AF:

0.0309

AC:

136

ESP6500EA

AF:

0.0467

AC:

402

ExAC

AF:

0.0464

AC:

5633

Asia WGS

AF:

0.0450

AC:

155

AN:

3478

EpiCase

AF:

0.0534

EpiControl

AF:

0.0550

ClinVar

ClinVar submissions

Significance:drug response

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Dihydropyrimidine dehydrogenase deficiency (1)

DPYD-related disorder (1)

capecitabine response - Toxicity (1)

fluorouracil response - Other (1)

fluorouracil response - Toxicity (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0044

MetaSVM

Uncertain

-0.076

MutationAssessor

Benign

1.7

PhyloP100

7.5

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.98

REVEL

Uncertain

0.30

Sift

Benign

0.057

Sift4G

Uncertain

0.055

Polyphen

1.0

Vest4

0.18

MPC

0.098

ClinPred

0.013

GERP RS

5.5

Varity_R

0.44

gMVP

0.62

Mutation Taster

=74/26

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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