rs56293913

Variant names:

• chr1-97573985-A-G
• rs56293913
• NM_000110.4:c.1129-15T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000110.4(DPYD):​c.1129-15T>C variant causes a 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 NM_000110.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 1.39
• Publications: 15 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=-0.79).
• BP6: Variant 1-97573985-A-G is Benign according to our data. Variant chr1-97573985-A-G is described in ClinVar as Benign. ClinVar VariationId is 100103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
DPYD	NM_000110.4	c.1129-15T>C		intron_variant	Intron 10 of 22	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8	c.1129-15T>C		intron_variant	Intron 10 of 22	1	NM_000110.4	ENSP00000359211.3

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

GnomAD2 exomes AF: 0.0956 AC: 23775 AN: 248638 AF XY: 0.0987

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 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

African (AFR) AF: 0.0581 AC: 1943 AN: 33414

American (AMR) AF: 0.0447 AC: 1990 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2867 AN: 26106

East Asian (EAS) AF: 0.0174 AC: 689 AN: 39612

South Asian (SAS) AF: 0.0769 AC: 6626 AN: 86154

European-Finnish (FIN) AF: 0.184 AC: 9807 AN: 53326

Middle Eastern (MID) AF: 0.168 AC: 970 AN: 5760

European-Non Finnish (NFE) AF: 0.107 AC: 119181 AN: 1111008

Other (OTH) AF: 0.0994 AC: 5997 AN: 60308

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

African (AFR) AF: 0.0590 AC: 2452 AN: 41564

American (AMR) AF: 0.0716 AC: 1094 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 402 AN: 3464

East Asian (EAS) AF: 0.0158 AC: 82 AN: 5184

South Asian (SAS) AF: 0.0618 AC: 298 AN: 4824

European-Finnish (FIN) AF: 0.185 AC: 1955 AN: 10584

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7894 AN: 67980

Other (OTH) AF: 0.0988 AC: 209 AN: 2116

Alfa AF: 0.104 Hom.: 1492

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

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. -

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Diasio Lab, Mayo Clinic

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not specified Benign:1

-

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	-0.79
CADD	Benign	5.9
DANN	Benign	0.81
PhyloP100		1.4
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: rs56293913; hg19: chr1-98039541; COSMIC: COSV64593293;