dbSNP rs56276561: DPYD:c.483+18G>A (chr1-97721492-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000110.4(DPYD):c.483+18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,610,268 control chromosomes in the GnomAD database, including 353 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 21 hom., cov: 32)

Exomes 𝑓: 0.019 ( 332 hom. )

Consequence

DPYD
NM_000110.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.246

Publications

28 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:

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=-0.81).

BP6

Variant 1-97721492-C-T is Benign according to our data. Variant chr1-97721492-C-T is described in ClinVar as Benign. ClinVar VariationId is 100117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0133 (2011/151696) while in subpopulation NFE AF = 0.0212 (1435/67724). AF 95% confidence interval is 0.0203. There are 21 homozygotes in GnomAd4. There are 954 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000110.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYD	NM_000110.4	MANE Select	c.483+18G>A		intron	N/A	NP_000101.2	Q12882-1
	DPYD	NM_001160301.1		c.483+18G>A		intron	N/A	NP_001153773.1	Q12882-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DPYD	ENST00000370192.8	TSL:1 MANE Select	c.483+18G>A	intron	N/A	ENSP00000359211.3	Q12882-1
DPYD	ENST00000306031.5	TSL:1	c.483+18G>A	intron	N/A	ENSP00000307107.5	Q12882-2
DPYD	ENST00000876340.1		c.483+18G>A	intron	N/A	ENSP00000546399.1

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

2011

AN:

151578

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00310

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.00759

Gnomad ASJ

AF:

0.00809

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.0199

Gnomad FIN

AF:

0.0143

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0212

Gnomad OTH

AF:

0.0101

GnomAD2 exomes

AF:

0.0145

AC:

3628

AN:

250088

AF XY:

0.0157

show subpopulations

Gnomad AFR exome

AF:

0.00296

Gnomad AMR exome

AF:

0.00459

Gnomad ASJ exome

AF:

0.00779

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0124

Gnomad NFE exome

AF:

0.0213

Gnomad OTH exome

AF:

0.0143

GnomAD4 exome

AF:

0.0194

AC:

28299

AN:

1458572

Hom.:

332

Cov.:

AF XY:

0.0195

AC XY:

14171

AN XY:

725612

show subpopulations

African (AFR)

AF:

0.00288

AC:

AN:

33318

American (AMR)

AF:

0.00494

AC:

220

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.00697

AC:

181

AN:

25980

East Asian (EAS)

AF:

0.000126

AC:

AN:

39608

South Asian (SAS)

AF:

0.0201

AC:

1730

AN:

86164

European-Finnish (FIN)

AF:

0.0132

AC:

707

AN:

53360

Middle Eastern (MID)

AF:

0.0131

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.0219

AC:

24306

AN:

1109636

Other (OTH)

AF:

0.0163

AC:

979

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

1266

2532

3798

5064

6330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

888

1776

2664

3552

4440

<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:

0.0133

AC:

2011

AN:

151696

Hom.:

Cov.:

AF XY:

0.0129

AC XY:

954

AN XY:

74134

show subpopulations

African (AFR)

AF:

0.00306

AC:

127

AN:

41462

American (AMR)

AF:

0.00758

AC:

115

AN:

15166

Ashkenazi Jewish (ASJ)

AF:

0.00809

AC:

AN:

3462

East Asian (EAS)

AF:

0.000582

AC:

AN:

5156

South Asian (SAS)

AF:

0.0199

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0143

AC:

152

AN:

10602

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0212

AC:

1435

AN:

67724

Other (OTH)

AF:

0.0105

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

107

214

320

427

534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0171

Hom.:

Bravo

AF:

0.0121

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.059

(source)

DANN

Benign

0.37

PhyloP100

-0.25

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over