rs1801267

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000110.4(DPYD):c.2657G>A(p.Arg886His) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,612,928 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

DPYD
NM_000110.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:3

Conservation

PhyloP100: 3.85

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 made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPYD	NM_000110.4 linkuse as main transcript	c.2657G>A	p.Arg886His	missense_variant	21/23	ENST00000370192.8
DPYD-AS1	NR_046590.1 linkuse as main transcript	n.64+2612C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPYD	ENST00000370192.8 linkuse as main transcript	c.2657G>A	p.Arg886His	missense_variant	21/23	1	NM_000110.4	P1	Q12882-1
DPYD-AS1	ENST00000422980.1 linkuse as main transcript	n.64+2612C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000439

AC:

AN:

250320

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135252

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000382

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1460840

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726720

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000367

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1997	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 05, 2022

Variant summary: DPYD c.2657G>A (p.Arg886His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250320 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency (4.4e-05 vs 0.0025), allowing no conclusion about variant significance. c.2657G>A has been reported in the literature in at least one individual with Dihydropyrimidine Dehydrogenase Deficiency, who carried the variant of interest as well as C29R, both in the homozygous state (Vreken_1997, Van Kuilenburg_1999). The variant has also been cited in the literature in panels testing cancer patients for chemotherapy toxicity. These reports do not provide unequivocal conclusions about association of the variant with Dihydropyrimidine Dehydrogenase Deficiency. The variant was reported in an E. Coli based expression system to have 25% residual acitvity, and in a mammalian cell system to have activity similar to wild-type (Vreken_1997, Offer_2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Pathogenic

0.21

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.82

MetaSVM

Pathogenic

0.80

MutationAssessor

Pathogenic

3.1

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.83

Sift

Uncertain

0.021

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.83

MutPred

0.70

Loss of sheet (P = 0.0104);

MVP

0.97

MPC

0.38

ClinPred

0.95

GERP RS

4.8

Varity_R

0.19

gMVP

0.72

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over