rs760663364

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000110.4(DPYD):c.1538C>T(p.Ala513Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A513G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

DPYD
NM_000110.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.44

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05535361).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYD	NM_000110.4 link	c.1538C>T	p.Ala513Val	missense_variant	Exon 13 of 23	ENST00000370192.8	NP_000101.2	Q12882-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8 link	c.1538C>T	p.Ala513Val	missense_variant	Exon 13 of 23	1	NM_000110.4	ENSP00000359211.3		Q12882-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151902

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250216

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135256

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460352

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726510

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151902

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74174

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency

Uncertain:2

May 15, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Aug 24, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1538C>T (p.A513V) alteration is located in exon 13 (coding exon 13) of the DPYD gene. This alteration results from a C to T substitution at nucleotide position 1538, causing the alanine (A) at amino acid position 513 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.18

DEOGEN2

Benign

0.054

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.53

M_CAP

Benign

0.032

MetaRNN

Benign

0.055

MetaSVM

Benign

-0.50

MutationAssessor

Benign

-0.26

PrimateAI

Benign

0.29

PROVEAN

Benign

1.0

REVEL

Benign

0.16

Sift

Benign

0.44

Sift4G

Benign

0.34

Polyphen

0.0

Vest4

0.060

MutPred

0.27

Loss of disorder (P = 0.0624);

MVP

0.82

MPC

0.055

ClinPred

0.028

GERP RS

4.3

Varity_R

0.024

gMVP

0.51

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