1-97579893-G-C

Variant names:

• chr1-97579893-G-C
• rs75017182
• NM_000110.4:c.1129-5923C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BS1_Supporting BS2

The NM_000110.4(DPYD):​c.1129-5923C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 152,204 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency: Genomes: 𝑓 0.013 (23 hom., cov: 33)
• Consequence: DPYD NM_000110.4 intron
• Clinical Significance: drug response reviewed by expert panel B:2 O:3
• Conservation: PhyloP100: 0.0950
• Publications: 102 publications found

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 Gene-Disease associations (from GenCC):

• dihydropyrimidine dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0131 (1993/152204) while in subpopulation NFE AF = 0.0214 (1454/67990). AF 95% confidence interval is 0.0205. There are 23 homozygotes in GnomAd4. There are 936 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYD	NM_000110.4	c.1129-5923C>G		intron_variant	Intron 10 of 22	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8	c.1129-5923C>G		intron_variant	Intron 10 of 22	1	NM_000110.4	ENSP00000359211.3

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1994 AN: 152086 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00747

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0100

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0131 AC: 1993 AN: 152204 Hom.: 23 Cov.: 33 AF XY: 0.0126 AC XY: 936 AN XY: 74402

African (AFR) AF: 0.00291 AC: 121 AN: 41554

American (AMR) AF: 0.00746 AC: 114 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0162 AC: 78 AN: 4812

European-Finnish (FIN) AF: 0.0142 AC: 150 AN: 10586

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0214 AC: 1454 AN: 67990

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00476 Hom.: 1

Bravo AF: 0.0120

Asia WGS AF: 0.00867 AC: 30 AN: 3476

ClinVar

Significance: drug response

Submissions summary: Benign:2 Other:3

Revision: reviewed by expert panel

Submissions by phenotype

DPYD-related disorder Benign:1

Jul 12, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

not provided Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DPYD: BS1, BS2 -

fluorouracil response - Toxicity Other:1

Oct 27, 2022

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

fluorouracil response - Other Other:1

Oct 27, 2022

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: Other

capecitabine response - Toxicity Other:1

Oct 27, 2022

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
BayesDel_noAF	Benign	-0.90
CADD	Pathogenic	35
DANN	Benign	0.68
PhyloP100		0.095
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.68		Position offset: 44
DS_DG_spliceai		0.77		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs75017182; hg19: chr1-98045449;