1-97515839-T-C

Position:

chr1-97515839-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_StrongBA1

The NM_000110.4(DPYD):c.1627A>G(p.Ile543Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,612,714 control chromosomes in the GnomAD database, including 31,976 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.19 ( 2802 hom., cov: 32)

Exomes 𝑓: 0.20 ( 29174 hom. )

Consequence

DPYD
NM_000110.4 missense

Scores

Clinical Significance

drug response reviewed by expert panel B:8O:3

Conservation

PhyloP100: 1.40

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00896588).

BP6

Variant 1-97515839-T-C is Benign according to our data. Variant chr1-97515839-T-C is described in ClinVar as [drug_response]. Clinvar id is 100092.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Benign=6, drug_response=2}. Variant chr1-97515839-T-C is described in Lovd as [Benign]. Variant chr1-97515839-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYD	NM_000110.4 linkuse as main transcript	c.1627A>G	p.Ile543Val	missense_variant	13/23	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.1627A>G	p.Ile543Val	missense_variant	13/23	1	NM_000110.4	ENSP00000359211.3		Q12882-1

Frequencies

GnomAD3 genomes

AF:

0.186

AC:

28219

AN:

151788

Hom.:

2791

Cov.:

show subpopulations

Gnomad AFR

AF:

0.158

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.237

Gnomad ASJ

AF:

0.194

Gnomad EAS

AF:

0.255

Gnomad SAS

AF:

0.0961

Gnomad FIN

AF:

0.167

Gnomad MID

AF:

0.156

Gnomad NFE

AF:

0.196

Gnomad OTH

AF:

0.184

GnomAD3 exomes

AF:

0.198

AC:

49519

AN:

250532

Hom.:

5373

AF XY:

0.189

AC XY:

25612

AN XY:

135378

show subpopulations

Gnomad AFR exome

AF:

0.158

Gnomad AMR exome

AF:

0.297

Gnomad ASJ exome

AF:

0.204

Gnomad EAS exome

AF:

0.254

Gnomad SAS exome

AF:

0.0944

Gnomad FIN exome

AF:

0.168

Gnomad NFE exome

AF:

0.197

Gnomad OTH exome

AF:

0.197

GnomAD4 exome

AF:

0.196

AC:

285727

AN:

1460808

Hom.:

29174

Cov.:

AF XY:

0.192

AC XY:

139533

AN XY:

726730

show subpopulations

Gnomad4 AFR exome

AF:

0.154

Gnomad4 AMR exome

AF:

0.294

Gnomad4 ASJ exome

AF:

0.195

Gnomad4 EAS exome

AF:

0.271

Gnomad4 SAS exome

AF:

0.0957

Gnomad4 FIN exome

AF:

0.168

Gnomad4 NFE exome

AF:

0.200

Gnomad4 OTH exome

AF:

0.192

GnomAD4 genome

AF:

0.186

AC:

28273

AN:

151906

Hom.:

2802

Cov.:

AF XY:

0.183

AC XY:

13615

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.159

Gnomad4 AMR

AF:

0.237

Gnomad4 ASJ

AF:

0.194

Gnomad4 EAS

AF:

0.255

Gnomad4 SAS

AF:

0.0964

Gnomad4 FIN

AF:

0.167

Gnomad4 NFE

AF:

0.196

Gnomad4 OTH

AF:

0.189

Alfa

AF:

0.198

Hom.:

7486

Bravo

AF:

0.195

TwinsUK

AF:

0.202

AC:

750

ALSPAC

AF:

0.204

AC:

786

ESP6500AA

AF:

0.155

AC:

684

ESP6500EA

AF:

0.198

AC:

1704

ExAC

AF:

0.192

AC:

23357

Asia WGS

AF:

0.192

AC:

669

AN:

3478

EpiCase

AF:

0.198

EpiControl

AF:

0.200

ClinVar

Significance: drug response

Submissions summary: Benign:8Other:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided

Benign:2Other:1

not provided, no classification provided	literature only	Diasio Lab, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	DPYD: BP4, BS1, BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 23, 2015

- -

DPYD-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

fluorouracil response - Toxicity

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

capecitabine response - Toxicity

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

9.5

DANN

Benign

0.96

DEOGEN2

Benign

0.16

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.92

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0090

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.49

PrimateAI

Benign

0.31

PROVEAN

Benign

0.73

REVEL

Benign

0.12

Sift

Benign

0.11

Sift4G

Benign

0.14

Polyphen

0.0

Vest4

0.036

MPC

0.048

ClinPred

0.0048

GERP RS

-3.1

Varity_R

0.029

gMVP

0.43

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