1-97098577-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000110.4(DPYD):c.2678A>G(p.Asn893Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

DPYD
NM_000110.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.16

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:40195): (DPYD antisense RNA 1)

DPYD-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.040837437).

BP6

Variant 1-97098577-T-C is Benign according to our data. Variant chr1-97098577-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3339417.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000039 (57/1460980) while in subpopulation EAS AF = 0.00141 (56/39588). AF 95% confidence interval is 0.00112. There are 0 homozygotes in GnomAdExome4. There are 25 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position FAILED quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYD	NM_000110.4 link	c.2678A>G	p.Asn893Ser	missense_variant	Exon 21 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.2678A>G	p.Asn893Ser	missense_variant	Exon 21 of 23	1	NM_000110.4	ENSP00000359211.3		Q12882-1
DPYD-AS1	ENST00000422980.1 link	n.64+2591T>C		intron_variant	Intron 1 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

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

GnomAD2 exomes

AF:

0.0000399

AC:

AN:

250708

AF XY:

0.0000369

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1460980

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726800

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33424

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44672

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26096

Gnomad4 EAS exome

AF:

0.00141

AC:

AN:

39588

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86238

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53352

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1111522

Gnomad4 Remaining exome

AF:

0.0000166

AC:

AN:

60334

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000387

AC:

0.000386548

AN:

0.000386548

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

DPYD-related disorder

Uncertain:1

May 09, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Benign:1

Jul 31, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DPYD c.2678A>G (p.Asn893Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 1606262 control chromosomes, predominantly at a frequency of 0.0013 within the East Asian subpopulation in the gnomAD database (v4.1 dataset). In addition, the variant was reported with an allele frequency of 0.0022 (i.e. 235 / 108520 alleles; no homozygotes), in healthy Japanese individuals in the jMorp database (PMID: 33179747). This frequency is close to the estimated maximum expected for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency (0.0025), suggesting that the variant might be benign. The variant, c.2678A>G, has been reported in the literature in Japanese individuals (e.g. Maekawa_2007), and at least two colon cancer patients were described who did not develop severe fluoropyrimidine-related toxicities (Kanai_2023). Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant resulted in a mild decrease in enzyme activity, corresponding to about 80% residual activity relative to the WT (Offer_2013), while a later study found that the variant N893S exhibited significantly lower activity, corresponding to ~62.8% of the WT (Hishinuma_2018). The following publications have been ascertained in the context of this evaluation (PMID: 17828463, 36524458, 23328581, 29769267, 29152729). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.076

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.74

M_CAP

Benign

0.027

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.52

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.40

REVEL

Benign

0.16

Sift

Benign

0.70

Sift4G

Benign

0.42

Polyphen

0.0

Vest4

0.17

MVP

0.87

MPC

0.047

ClinPred

0.015

GERP RS

3.4

Varity_R

0.054

gMVP

0.41

Mutation Taster

=98/2

polymorphism

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