rs1042482

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 0.265

Publications

8 publications found

Variant links:

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

DPYD links:

ENSG00000296260 (HGNC:):

ENSG00000296260 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
DPYD	NM_000110.4 link	c.*573G>A		3_prime_UTR_variant	Exon 23 of 23	ENST00000370192.8	NP_000101.2	Q12882-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8 link	c.*573G>A		3_prime_UTR_variant	Exon 23 of 23	1	NM_000110.4	ENSP00000359211.3		Q12882-1
ENSG00000296260	ENST00000737657.1 link	n.550-3344C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0625

AC:

9507

AN:

152120

Hom.:

400

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.0766

AC XY:

718

AN XY:

9378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.0428

AC:

108

AN:

2526

Ashkenazi Jewish (ASJ)

AF:

0.0385

AC:

AN:

208

East Asian (EAS)

AF:

0.108

AC:

AN:

882

South Asian (SAS)

AF:

0.147

AC:

332

AN:

2258

European-Finnish (FIN)

AF:

0.0673

AC:

AN:

490

Middle Eastern (MID)

AF:

0.0263

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0618

AC:

644

AN:

10424

Other (OTH)

AF:

0.0571

AC:

AN:

718

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

121

182

242

303

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0625

AC:

9512

AN:

152238

Hom.:

400

Cov.:

AF XY:

0.0639

AC XY:

4757

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0146

AC:

606

AN:

41568

American (AMR)

AF:

0.0453

AC:

692

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0663

AC:

230

AN:

3468

East Asian (EAS)

AF:

0.129

AC:

671

AN:

5188

South Asian (SAS)

AF:

0.177

AC:

855

AN:

4826

European-Finnish (FIN)

AF:

0.0888

AC:

941

AN:

10594

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0790

AC:

5373

AN:

67994

Other (OTH)

AF:

0.0554

AC:

117

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

447

894

1341

1788

2235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

248

372

496

620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0722

Hom.:

1141

Bravo

AF:

0.0564

Asia WGS

AF:

0.189

AC:

656

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1Other:1

Diasio Lab, Mayo Clinic

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dihydropyrimidine dehydrogenase deficiency

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.63

PhyloP100

0.27

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over