rs55886062

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS3PP3

The NM_000110.4(DPYD):c.1679T>G(p.Ile560Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000655 in 1,612,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). ClinVar reports functional evidence for this variant: "SCV000321560: Published functional studies demonstrate that this variant reduces DPD enzyme activity (PMID:23328581)" and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00068 ( 0 hom. )

Consequence

DPYD
NM_000110.4 missense

Scores

Clinical Significance

drug response reviewed by expert panel P:12O:5

Conservation

PhyloP100: 8.76

Publications

316 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: Uncertain_significance. The variant received 5 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000321560: Published functional studies demonstrate that this variant reduces DPD enzyme activity (PMID: 23328581); SCV001748682: Experimental evidence evaluating an impact on protein function demonstrated that the variant resulted in a decreased enzyme activity, corresponding to about 75% reduction relative to the WT (Offer_2014),; SCV002768091: Functional studies show up to a 75% reduction in activity relative to wild-type (PMIDs: 23328581, 29152729).; SCV005114305: "In an assay testing DPYD function, this variant showed a functionally abnormal result" (Offer, 2013).

PP3

MetaRNN computational evidence supports a deleterious effect, 0.832

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYD	NM_000110.4	MANE Select	c.1679T>G	p.Ile560Ser	missense	Exon 13 of 23	NP_000101.2	Q12882-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DPYD	ENST00000370192.8	TSL:1 MANE Select	c.1679T>G	p.Ile560Ser	missense	Exon 13 of 23	ENSP00000359211.3	Q12882-1
DPYD	ENST00000876340.1		c.1847T>G	p.Ile616Ser	missense	Exon 14 of 24	ENSP00000546399.1
DPYD	ENST00000969915.1		c.1679T>G	p.Ile560Ser	missense	Exon 13 of 24	ENSP00000639974.1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000319

AC:

AN:

250646

AF XY:

0.000310

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.000654

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000682

AC:

997

AN:

1460868

Hom.:

Cov.:

AF XY:

0.000632

AC XY:

459

AN XY:

726764

show subpopulations

African (AFR)

AF:

0.0000898

AC:

AN:

33422

American (AMR)

AF:

0.00

AC:

AN:

44622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000853

AC:

948

AN:

1111332

Other (OTH)

AF:

0.000663

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

112

169

225

281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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:

0.000388

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41564

American (AMR)

AF:

0.0000657

AC:

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

67950

Other (OTH)

AF:

0.00

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000624

Hom.:

Bravo

AF:

0.000325

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000346

AC:

EpiCase

AF:

0.000655

EpiControl

AF:

0.000830

ClinVar

ClinVar submissions

Significance:drug response

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Dihydropyrimidine dehydrogenase deficiency (5)

Inborn genetic diseases (1)

capecitabine response - Toxicity (1)

fluorouracil response - Other (1)

fluorouracil response - Toxicity (1)

tegafur response - Toxicity (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

-0.024

MutationAssessor

Uncertain

2.2

PhyloP100

8.8

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-5.1

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.96

MVP

0.99

MPC

0.39

ClinPred

0.82

GERP RS

5.2

Varity_R

0.70

gMVP

0.95

Mutation Taster

=16/84

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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