1-97515865-C-T

Variant names:

• chr1-97515865-C-T
• rs1801158
• NM_000110.4:c.1601G>A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Strong BS1 BS2

The NM_000110.4(DPYD):​c.1601G>A​(p.Ser534Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0188 in 1,612,856 control chromosomes in the GnomAD database, including 337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Synonymous variant affecting the same amino acid position (i.e. S534S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (26 hom., cov: 32)
  • Exomes 𝑓: 0.019 (311 hom.)
• Consequence: DPYD NM_000110.4 missense
• Clinical Significance: drug response reviewed by expert panel U:1 B:7 O:3
• Conservation: PhyloP100: 5.71

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0098076165).
• BP6: Variant 1-97515865-C-T is Benign according to our data. Variant chr1-97515865-C-T is described in ClinVar as [drug_response]. Clinvar id is 100094.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, drug_response=2, Benign=3, Uncertain_significance=1, not_provided=1}. Variant chr1-97515865-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0137 (2086/152056) while in subpopulation NFE AF= 0.0196 (1330/67912). AF 95% confidence interval is 0.0187. There are 26 homozygotes in gnomad4. There are 1012 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYD	NM_000110.4	c.1601G>A	p.Ser534Asn	missense_variant	Exon 13 of 23	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8	c.1601G>A	p.Ser534Asn	missense_variant	Exon 13 of 23	1	NM_000110.4	ENSP00000359211.3

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2084 AN: 151938 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00396

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0173

GnomAD3 exomes AF: 0.0147 AC: 3683 AN: 250562 Hom.: 40 AF XY: 0.0147 AC XY: 1985 AN XY: 135402

Gnomad AFR exome AF: 0.00382

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0302

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00863

Gnomad FIN exome AF: 0.0135

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0175

GnomAD4 exome AF: 0.0193 AC: 28204 AN: 1460800 Hom.: 311 Cov.: 33 AF XY: 0.0189 AC XY: 13709 AN XY: 726732

Gnomad4 AFR exome AF: 0.00320

Gnomad4 AMR exome AF: 0.0120

Gnomad4 ASJ exome AF: 0.0316

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00867

Gnomad4 FIN exome AF: 0.0139

Gnomad4 NFE exome AF: 0.0215

Gnomad4 OTH exome AF: 0.0196

GnomAD4 genome AF: 0.0137 AC: 2086 AN: 152056 Hom.: 26 Cov.: 32 AF XY: 0.0136 AC XY: 1012 AN XY: 74312

Gnomad4 AFR AF: 0.00395

Gnomad4 AMR AF: 0.0152

Gnomad4 ASJ AF: 0.0331

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.0152

Gnomad4 NFE AF: 0.0196

Gnomad4 OTH AF: 0.0171

Alfa AF: 0.0197 Hom.: 59

Bravo AF: 0.0133

TwinsUK AF: 0.0216 AC: 80

ALSPAC AF: 0.0202 AC: 78

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0202 AC: 174

ExAC AF: 0.0141 AC: 1712

Asia WGS AF: 0.00491 AC: 18 AN: 3478

EpiCase AF: 0.0246

EpiControl AF: 0.0240

ClinVar

Significance: drug response

Submissions summary: Uncertain:1 Benign:7 Other:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3 Other:1

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DPYD: BS1, BS2 -

-

Diasio Lab, Mayo Clinic

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 08, 2017

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dihydropyrimidine dehydrogenase deficiency Uncertain:1 Benign:2

Aug 03, 2015

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

Mar 29, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DPYD-related disorder Benign:1

Feb 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

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

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0098	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.26
MPC		0.055
ClinPred		0.032	T
GERP RS		5.2
Varity_R		0.48
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1801158; hg19: chr1-97981421; COSMIC: COSV64597757;