1-97579893-G-C

Position:

• chr1-97579893-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Strong BS1 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

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 -12 ACMG points.

• BP6: Variant 1-97579893-G-C is Benign according to our data. Variant chr1-97579893-G-C is described in ClinVar as [drug_response]. Clinvar id is 635263.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=1, drug_response=3}.
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYD	NM_000110.4	c.1129-5923C>G		intron_variant		ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8	c.1129-5923C>G		intron_variant		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

Gnomad4 AFR AF: 0.00291

Gnomad4 AMR AF: 0.00746

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.0142

Gnomad4 NFE AF: 0.0214

Gnomad4 OTH AF: 0.00993

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2021

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

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

DPYD: BS1, BS2 -

fluorouracil response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Oct 27, 2022

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

drug response, reviewed by expert panel

curation

PharmGKB

Oct 27, 2022

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

drug response, reviewed by expert panel

curation

PharmGKB

Oct 27, 2022

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

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs75017182; hg19: chr1-98045449;