chr1-97515815-C-T

Position:

chr1-97515815-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_000110.4(DPYD):c.1651G>A(p.Ala551Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000775 in 1,612,844 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

DPYD
NM_000110.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:3

Conservation

PhyloP100: 7.41

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 Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.849

PP5

Variant 1-97515815-C-T is Pathogenic according to our data. Variant chr1-97515815-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 298287.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYD	NM_000110.4 linkuse as main transcript	c.1651G>A	p.Ala551Thr	missense_variant	13/23	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.1651G>A	p.Ala551Thr	missense_variant	13/23	1	NM_000110.4	ENSP00000359211	P1	Q12882-1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151896

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000120

AC:

AN:

250566

Hom.:

AF XY:

0.000148

AC XY:

AN XY:

135382

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000707

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000808

AC:

118

AN:

1460830

Hom.:

Cov.:

AF XY:

0.0000963

AC XY:

AN XY:

726734

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000719

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000126

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency

Pathogenic:2Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 06, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 01, 2022	Variant summary: DPYD c.1651G>A (p.Ala551Thr) results in a non-conservative amino acid change located in the Dihydroorotate dehydrogenase domain (IPR005720) of 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 0.00012 in 250566 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency (0.00012 vs 0.0025), allowing no conclusion about variant significance. c.1651G>A has been reported in the literature as a homozygous genotype in at-least three individuals affected with Dihydropyrimidine Dehydrogenase Deficiency confirmed by supportive biochemical findings demonstrating an accumulation of Thymine and Uracil. (example, Van Kuilenburg_2005, Chen_2014). These data indicate that the variant is very likely to be associated with disease. The Dutch Pharmacogenetics Working Group (DPWG) guideline for the genedrug interaction of DPYD and fluoropyrimidines lists this variant among those that may be fully dysfunctional but lack sufficient evidence to associate a predicted DPYD enzyme activity and the onset of severe fluoropyrimidine-induced toxicity (Lunenburg_2020). To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters cite overlapping evidence utilized in the context of this evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The DPYD c.1651G>A (p.Ala551Thr) missense variant has been reported in at least two studies in which it is found in at least two siblings with dihydropyrimidine dehydrogenase (DPD) deficiency in a homozygous state (van Kuilenburg et al. 2005; Chen et al. 2014). The variant is also found in four unaffected parents of DPD deficiency patients (van Kuilenburg et al. 2005; Chen et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00073 in the South Asian population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Ala551Thr variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for diyhydropyrimidine dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

DPYD-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2022

The DPYD c.1651G>A variant is predicted to result in the amino acid substitution p.Ala551Thr. This variant was reported homozygous in two siblings with Dihydropyrimidine dehydrogenase deficiency (Chen BC et al 2014. PubMed ID: 25565930). Both siblings showed excessive excretion of uracil and thymine. In addition, this variant was also found in the heterozygous state in both consanguineous parents of a patient with biochemical findings consistent with dihydropyrimidine dehydrogenase deficiency, but DNA from this patient was not available for testing (Van Kuilenburg et al. 2005. PubMed ID: 15899693). This variant is reported in 0.072% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-97981371-C-T). This variant is interpreted as likely pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2018

The A551T variant in the DPYD gene has been reported previously in two siblings with DPD deficiency (Chen et al.., 2014). While not observed in the homozygous state, the A551T variant is observed in 12/16474 (0.073%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). The A551T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret A551T as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.85

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.9

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.76

MVP

0.97

MPC

0.36

ClinPred

0.98

GERP RS

5.0

Varity_R

0.83

gMVP

0.93

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