rs56005131

Positions:

chr1-97234991-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_000110.4(DPYD):c.2303C>A(p.Thr768Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000355 in 1,613,978 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 4 hom. )

Consequence

DPYD
NM_000110.4 missense

Scores

Clinical Significance

drug response reviewed by expert panel U:4B:2O:2

Conservation

PhyloP100: 2.67

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:):

DPYD-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.076833904).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000204 (31/152178) while in subpopulation EAS AF= 0.00503 (26/5164). AF 95% confidence interval is 0.00353. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYD	NM_000110.4 linkuse as main transcript	c.2303C>A	p.Thr768Lys	missense_variant	19/23	ENST00000370192.8	NP_000101.2	Q12882-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8 linkuse as main transcript	c.2303C>A	p.Thr768Lys	missense_variant	19/23	1	NM_000110.4	ENSP00000359211.3		Q12882-1
DPYD-AS1	ENST00000422980.1 linkuse as main transcript	n.65-30423G>T		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00502

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000211

AC:

AN:

251018

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00251

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000371

AC:

542

AN:

1461800

Hom.:

Cov.:

AF XY:

0.000370

AC XY:

269

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0129

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000204

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00503

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000189

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: drug response

Submissions summary: Uncertain:4Benign:2Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency

Uncertain:1Benign:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Dec 15, 2017	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2020	Identified with a second missense variant, phase unknown, in a female Japanese individual with very low dihydropyrimidine dehydrogenase (DPD) activity and protein expression levels (Ogura et al., 2005); Functional studies are discordant in their conclusions regarding enzyme activity (Offer et al., 2014; Ogura et al., 2005); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in the heterozygous state in 3-6% of Japanese individuals (Maekawa et al., 2007; Okamoto et al., 2007); This variant is associated with the following publications: (PMID: 29769267, 20920994, 17876700, 19287123, 17828463, 24163242, 21498394, 16033824, 24648345, 32619063, 32707991) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2016	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2021

The c.2303C>A (p.T768K) alteration is located in exon 19 (coding exon 19) of the DPYD gene. This alteration results from a C to A substitution at nucleotide position 2303, causing the threonine (T) at amino acid position 768 to be replaced by a lysine (K). The in silico prediction for the p.T768K alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

DPYD-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 13, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

fluorouracil response - Other

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

May 25, 2021

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: Other

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.20

Eigen

Benign

-0.043

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.049

MetaRNN

Benign

0.077

MetaSVM

Benign

-0.55

MutationAssessor

Benign

-0.61

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.46

REVEL

Uncertain

0.49

Sift

Benign

0.038

Sift4G

Benign

0.11

Polyphen

0.58

Vest4

0.82

MVP

0.89

MPC

0.072

ClinPred

0.040

GERP RS

5.7

Varity_R

0.34

gMVP

0.78

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