rs1042482

Positions:

• chr1-97078403-C-T

Variant summary

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

The NM_000110.4(DPYD):​c.*573G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0634 in 169,874 control chromosomes in the GnomAD database, including 453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (400 hom., cov: 32)
  • Exomes 𝑓: 0.072 (53 hom.)
• Consequence: DPYD NM_000110.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.265

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=-0.84).
• BP6: Variant 1-97078403-C-T is Benign according to our data. Variant chr1-97078403-C-T is described in ClinVar as [Benign]. Clinvar id is 100067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYD	NM_000110.4	c.*573G>A		3_prime_UTR_variant	23/23	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8	c.*573G>A		3_prime_UTR_variant	23/23	1	NM_000110.4	ENSP00000359211	P1

Frequencies

GnomAD3 genomes AF: 0.0625 AC: 9507 AN: 152120 Hom.: 400 Cov.: 32

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0448

Gnomad ASJ AF: 0.0663

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.0888

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0790

Gnomad OTH AF: 0.0550

GnomAD4 exome AF: 0.0716 AC: 1262 AN: 17636 Hom.: 53 Cov.: 0 AF XY: 0.0766 AC XY: 718 AN XY: 9378

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0428

Gnomad4 ASJ exome AF: 0.0385

Gnomad4 EAS exome AF: 0.108

Gnomad4 SAS exome AF: 0.147

Gnomad4 FIN exome AF: 0.0673

Gnomad4 NFE exome AF: 0.0618

Gnomad4 OTH exome AF: 0.0571

GnomAD4 genome AF: 0.0625 AC: 9512 AN: 152238 Hom.: 400 Cov.: 32 AF XY: 0.0639 AC XY: 4757 AN XY: 74430

Gnomad4 AFR AF: 0.0146

Gnomad4 AMR AF: 0.0453

Gnomad4 ASJ AF: 0.0663

Gnomad4 EAS AF: 0.129

Gnomad4 SAS AF: 0.177

Gnomad4 FIN AF: 0.0888

Gnomad4 NFE AF: 0.0790

Gnomad4 OTH AF: 0.0554

Alfa AF: 0.0743 Hom.: 764

Bravo AF: 0.0564

Asia WGS AF: 0.189 AC: 656 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	-	- -

Dihydropyrimidine dehydrogenase deficiency Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.9
DANN	Benign	0.63

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: rs1042482; hg19: chr1-97543959;