rs45589337

Positions:

chr1-97679170-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000370192.8(DPYD):c.775A>G(p.Lys259Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00665 in 1,564,148 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0051 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0068 ( 39 hom. )

Consequence

DPYD
ENST00000370192.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 3.87

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014378965).

BP6

Variant 1-97679170-T-C is Benign according to our data. Variant chr1-97679170-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235464.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1, Likely_benign=2}. Variant chr1-97679170-T-C is described in Lovd as [Benign]. Variant chr1-97679170-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00514 (783/152264) while in subpopulation NFE AF= 0.00748 (509/68008). AF 95% confidence interval is 0.00695. There are 6 homozygotes in gnomad4. There are 351 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYD	NM_000110.4 linkuse as main transcript	c.775A>G	p.Lys259Glu	missense_variant	8/23	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8 linkuse as main transcript	c.775A>G	p.Lys259Glu	missense_variant	8/23	1	NM_000110.4	ENSP00000359211	P1	Q12882-1

Frequencies

GnomAD3 genomes

AF:

0.00514

AC:

782

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.0181

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.00594

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00748

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00620

AC:

1365

AN:

220112

Hom.:

AF XY:

0.00636

AC XY:

753

AN XY:

118422

show subpopulations

Gnomad AFR exome

AF:

0.00146

Gnomad AMR exome

AF:

0.00316

Gnomad ASJ exome

AF:

0.0146

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00501

Gnomad FIN exome

AF:

0.00712

Gnomad NFE exome

AF:

0.00822

Gnomad OTH exome

AF:

0.00852

GnomAD4 exome

AF:

0.00681

AC:

9620

AN:

1411884

Hom.:

Cov.:

AF XY:

0.00679

AC XY:

4766

AN XY:

701658

show subpopulations

Gnomad4 AFR exome

AF:

0.000739

Gnomad4 AMR exome

AF:

0.00342

Gnomad4 ASJ exome

AF:

0.0162

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00521

Gnomad4 FIN exome

AF:

0.00891

Gnomad4 NFE exome

AF:

0.00719

Gnomad4 OTH exome

AF:

0.00664

GnomAD4 genome

AF:

0.00514

AC:

783

AN:

152264

Hom.:

Cov.:

AF XY:

0.00471

AC XY:

351

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00137

Gnomad4 AMR

AF:

0.00360

Gnomad4 ASJ

AF:

0.0181

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00518

Gnomad4 FIN

AF:

0.00594

Gnomad4 NFE

AF:

0.00748

Gnomad4 OTH

AF:

0.00522

Alfa

AF:

0.00744

Hom.:

Bravo

AF:

0.00511

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00747

AC:

ExAC

AF:

0.00611

AC:

736

Asia WGS

AF:

0.00145

AC:

AN:

3464

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 21, 2022	Variant summary: DPYD c.775A>G (p.Lys259Glu) results in a conservative amino acid change located in the FAD/NAD(P)-binding domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0061 in 251782 control chromosomes in the gnomAD database, including 12 homozygotes. The observed variant frequency is approximately 2.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency phenotype (0.0025), strongly suggesting that the variant is benign. c.775A>G has been reported in the literature in individuals affected with 5-FU-related toxicity (example Gross_2003, Schwab_2008, Harismendy_2013, Garcia-Gonzalez_2020). One of these studies described that DPYD enzyme activity measured in the cytosolic fraction of PBMCs from a heterozygous patient was in the normal range (Gross_2003). These reports do not provide unequivocal conclusions about association of the variant with Dihydropyrimidine Dehydrogenase Deficiency. At least one publication reports evaluating the impact of the variant on protein function in an in vitro expression system and found no damaging effect on enzymatic activity (Offer_2014). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three laboratories classified the variant as benign, one as likely benign, and one as VUS. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22935545, 14635116, 19473056, 24648345) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	DPYD: BS1, BS2 -

Dihydropyrimidine dehydrogenase deficiency

Uncertain:1Benign: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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

0.098

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

MetaRNN

Benign

0.014

MetaSVM

Uncertain

0.42

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.61

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0060

Polyphen

0.34

Vest4

0.85

MVP

0.92

MPC

0.093

ClinPred

0.025

GERP RS

4.5

Varity_R

0.37

gMVP

0.81

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