1-97883329-A-G

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.85T>C(p.Cys29Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,612,580 control chromosomes in the GnomAD database, including 44,075 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C29Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.27 ( 6329 hom., cov: 32)

Exomes 𝑓: 0.22 ( 37746 hom. )

Consequence

DPYD
NM_000110.4 missense

Scores

Clinical Significance

drug response reviewed by expert panel P:1B:3O:2

Conservation

PhyloP100: 1.65

Publications

239 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=0.0027006269).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYD	NM_000110.4 link	c.85T>C	p.Cys29Arg	missense_variant	Exon 2 of 23	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DPYD	ENST00000370192.8 link	c.85T>C	p.Cys29Arg	missense_variant	Exon 2 of 23	1	NM_000110.4	ENSP00000359211.3
DPYD	ENST00000306031.5 link	c.85T>C	p.Cys29Arg	missense_variant	Exon 2 of 6	1		ENSP00000307107.5
DPYD	ENST00000460019.1 link	n.160T>C		non_coding_transcript_exon_variant	Exon 2 of 3	2
DPYD	ENST00000646851.1 link	n.734T>C		non_coding_transcript_exon_variant	Exon 6 of 6

Frequencies

GnomAD3 genomes

AF:

0.273

AC:

41507

AN:

151914

Hom.:

6303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.403

Gnomad AMI

AF:

0.220

Gnomad AMR

AF:

0.247

Gnomad ASJ

AF:

0.111

Gnomad EAS

AF:

0.0721

Gnomad SAS

AF:

0.248

Gnomad FIN

AF:

0.282

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.225

Gnomad OTH

AF:

0.256

GnomAD4 exome

AF:

0.221

AC:

323245

AN:

1460548

Hom.:

37746

Cov.:

AF XY:

0.222

AC XY:

161542

AN XY:

726642

show subpopulations

African (AFR)

AF:

0.413

AC:

13788

AN:

33424

American (AMR)

AF:

0.214

AC:

9572

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

3005

AN:

26096

East Asian (EAS)

AF:

0.0516

AC:

2045

AN:

39624

South Asian (SAS)

AF:

0.253

AC:

21801

AN:

86222

European-Finnish (FIN)

AF:

0.288

AC:

15362

AN:

53376

Middle Eastern (MID)

AF:

0.234

AC:

1350

AN:

5758

European-Non Finnish (NFE)

AF:

0.219

AC:

242879

AN:

1111048

Other (OTH)

AF:

0.223

AC:

13443

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

13665

27330

40994

54659

68324

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8310

16620

24930

33240

41550

<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:

0.274

AC:

41589

AN:

152032

Hom.:

6329

Cov.:

AF XY:

0.273

AC XY:

20262

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.404

AC:

16752

AN:

41462

American (AMR)

AF:

0.248

AC:

3779

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

384

AN:

3470

East Asian (EAS)

AF:

0.0719

AC:

370

AN:

5144

South Asian (SAS)

AF:

0.247

AC:

1191

AN:

4822

European-Finnish (FIN)

AF:

0.282

AC:

2987

AN:

10582

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.225

AC:

15323

AN:

67972

Other (OTH)

AF:

0.254

AC:

537

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1496

2992

4487

5983

7479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

418

836

1254

1672

2090

<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:

0.229

Hom.:

20285

Bravo

AF:

0.273

ClinVar

Significance: drug response

Submissions summary: Pathogenic:1Benign:3Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dihydropyrimidine dehydrogenase deficiency

Pathogenic:1

Dec 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

not specified

Benign:1

May 04, 2022

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

0.043

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DEOGEN2

Benign

0.059

T;.

LIST_S2

Benign

0.023

T;T

MetaRNN

Benign

0.0027

T;T

MutationAssessor

Benign

0.0

.;.

PhyloP100

1.6

PROVEAN

Benign

0.0

.;.

Sift

Pathogenic

0.0

.;.

Sift4G

Benign

0.43

T;T

Vest4

0.085

gMVP

0.61

Splicing

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