rs56276561

Variant names:

• chr1-97721492-C-T
• rs56276561
• NM_000110.4:c.483+18G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.246
• Publications: 26 publications found

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

ACMG classification

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYD	NM_000110.4	c.483+18G>A		intron_variant	Intron 5 of 22	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8	c.483+18G>A		intron_variant	Intron 5 of 22	1	NM_000110.4	ENSP00000359211.3
DPYD	ENST00000306031.5	c.483+18G>A		intron_variant	Intron 5 of 5	1		ENSP00000307107.5
DPYD	ENST00000474241.1	n.145+18G>A		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2011 AN: 151578 Hom.: 21 Cov.: 32

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

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.: 31 AF XY: 0.0195 AC XY: 14171 AN XY: 725612

African (AFR) AF: 0.00288 AC: 96 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: 5 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: 75 AN: 5740

European-Non Finnish (NFE) AF: 0.0219 AC: 24306 AN: 1109636

Other (OTH) AF: 0.0163 AC: 979 AN: 60200

GnomAD4 genome AF: 0.0133 AC: 2011 AN: 151696 Hom.: 21 Cov.: 32 AF XY: 0.0129 AC XY: 954 AN XY: 74134

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: 28 AN: 3462

East Asian (EAS) AF: 0.000582 AC: 3 AN: 5156

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4818

European-Finnish (FIN) AF: 0.0143 AC: 152 AN: 10602

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0212 AC: 1435 AN: 67724

Other (OTH) AF: 0.0105 AC: 22 AN: 2100

Alfa AF: 0.0171 Hom.: 8

Bravo AF: 0.0121

Asia WGS AF: 0.0100 AC: 35 AN: 3478

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

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Diasio Lab, Mayo Clinic

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.059
DANN	Benign	0.37
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs56276561; hg19: chr1-98187048;