chr1-97450168-A-G

Position:

chr1-97450168-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000110.4(DPYD):c.1796T>C(p.Met599Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000057 in 1,613,814 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

DPYD
NM_000110.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 7.15

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYD	NM_000110.4 linkuse as main transcript	c.1796T>C	p.Met599Thr	missense_variant	14/23	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.1796T>C	p.Met599Thr	missense_variant	14/23	1	NM_000110.4	ENSP00000359211.3		Q12882-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000677

AC:

AN:

251236

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000547

AC:

AN:

1461622

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727104

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:

0.0000693

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74360

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:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000893

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 13, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 10, 2024

Variant summary: DPYD c.1796T>C (p.Met599Thr) results in a non-conservative amino acid change located in the Dihydroorotate dehydrogenase domain (IPR005720) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251236 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency (6.8e-05 vs 0.0025), allowing no conclusion about variant significance. c.1796T>C has been reported in the literature in one heterozygous individual affected with 5-FU toxicity (Ofverholm_2009). This report does not provide unequivocal conclusions about association of the variant with Dihydropyrimidine Dehydrogenase Deficiency as benign variants have also been associated with 5-FU toxicity. Enzyme activity assays using protein lysates from HEK293T/c17 transfected cells show that the variant had WT levels of DPD metabolic activity (Offer_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24648345, 19822137). ClinVar contains an entry for this variant (Variation ID: 550673). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

DPYD: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.22

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.75

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.63

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.73

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.98

REVEL

Uncertain

0.38

Sift

Benign

0.39

Sift4G

Benign

0.40

Polyphen

0.0

Vest4

0.76

MVP

0.84

MPC

0.061

ClinPred

0.064

GERP RS

4.2

Varity_R

0.20

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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