rs56293913

Positions:

• chr1-97573985-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000370192.8(DPYD):​c.1129-15T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,612,456 control chromosomes in the GnomAD database, including 9,385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (849 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8536 hom.)
• Consequence: DPYD ENST00000370192.8 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 1.39

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-97573985-A-G is Benign according to our data. Variant chr1-97573985-A-G is described in ClinVar as [Benign]. Clinvar id is 100103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-97573985-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYD	NM_000110.4	c.1129-15T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8	c.1129-15T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000110.4	ENSP00000359211	P1

Frequencies

GnomAD3 genomes AF: 0.0957 AC: 14560 AN: 152086 Hom.: 849 Cov.: 32

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.0717

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.0621

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.0989

GnomAD3 exomes AF: 0.0956 AC: 23775 AN: 248638 Hom.: 1419 AF XY: 0.0987 AC XY: 13273 AN XY: 134420

Gnomad AFR exome AF: 0.0582

Gnomad AMR exome AF: 0.0413

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.0155

Gnomad SAS exome AF: 0.0745

Gnomad FIN exome AF: 0.189

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.103 AC: 150070 AN: 1460252 Hom.: 8536 Cov.: 32 AF XY: 0.103 AC XY: 75163 AN XY: 726364

Gnomad4 AFR exome AF: 0.0581

Gnomad4 AMR exome AF: 0.0447

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.0174

Gnomad4 SAS exome AF: 0.0769

Gnomad4 FIN exome AF: 0.184

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.0994

GnomAD4 genome AF: 0.0957 AC: 14566 AN: 152204 Hom.: 849 Cov.: 32 AF XY: 0.0971 AC XY: 7226 AN XY: 74408

Gnomad4 AFR AF: 0.0590

Gnomad4 AMR AF: 0.0716

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.0158

Gnomad4 SAS AF: 0.0618

Gnomad4 FIN AF: 0.185

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.0988

Alfa AF: 0.107 Hom.: 203

Bravo AF: 0.0853

Asia WGS AF: 0.0430 AC: 149 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Diasio Lab, Mayo Clinic	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.9
DANN	Benign	0.81

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

Other links and lift over

dbSNP: rs56293913; hg19: chr1-98039541; COSMIC: COSV64593293;