rs1801265

Positions:

• chr1-97883329-A-G
• chr1-97883329-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Strong BA1

The ENST00000370192.8(DPYD):​c.85T>C​(p.Cys29Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,612,580 control chromosomes in the GnomAD database, including 44,075 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C29Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.27 (6329 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37746 hom.)
• Consequence: DPYD ENST00000370192.8 missense
• Clinical Significance: drug response reviewed by expert panel P:1 B:3 O:2
• Conservation: PhyloP100: 1.65

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=0.0027006269).
• BP6: Variant 1-97883329-A-G is Benign according to our data. Variant chr1-97883329-A-G is described in ClinVar as [drug_response]. Clinvar id is 435.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=3, drug_response=2}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYD	NM_000110.4	c.85T>C	p.Cys29Arg	missense_variant	2/23	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8	c.85T>C	p.Cys29Arg	missense_variant	2/23	1	NM_000110.4	ENSP00000359211	P1
DPYD	ENST00000306031.5	c.85T>C	p.Cys29Arg	missense_variant	2/6	1		ENSP00000307107
DPYD	ENST00000460019.1	n.160T>C		non_coding_transcript_exon_variant	2/3	2
DPYD	ENST00000646851.1	n.734T>C		non_coding_transcript_exon_variant	6/6

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41507 AN: 151914 Hom.: 6303 Cov.: 32

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0721

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.256

GnomAD4 exome AF: 0.221 AC: 323245 AN: 1460548 Hom.: 37746 Cov.: 32 AF XY: 0.222 AC XY: 161542 AN XY: 726642

Gnomad4 AFR exome AF: 0.413

Gnomad4 AMR exome AF: 0.214

Gnomad4 ASJ exome AF: 0.115

Gnomad4 EAS exome AF: 0.0516

Gnomad4 SAS exome AF: 0.253

Gnomad4 FIN exome AF: 0.288

Gnomad4 NFE exome AF: 0.219

Gnomad4 OTH exome AF: 0.223

GnomAD4 genome AF: 0.274 AC: 41589 AN: 152032 Hom.: 6329 Cov.: 32 AF XY: 0.273 AC XY: 20262 AN XY: 74276

Gnomad4 AFR AF: 0.404

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.0719

Gnomad4 SAS AF: 0.247

Gnomad4 FIN AF: 0.282

Gnomad4 NFE AF: 0.225

Gnomad4 OTH AF: 0.254

Alfa AF: 0.221 Hom.: 9785

Bravo AF: 0.273

ClinVar

Significance: drug response

Submissions summary: Pathogenic:1 Benign:3 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 20, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 20, 2017	- -

Dihydropyrimidine dehydrogenase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1997

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

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

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	0.043
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DEOGEN2	Benign	0.059	T;.
LIST_S2	Benign	0.023	T;T
MetaRNN	Benign	0.0027	T;T
Sift4G	Benign	0.43	T;T
Vest4		0.085
gMVP		0.61

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1801265; hg19: chr1-98348885;