rs291593

Variant names:

• chr1-97078196-G-A
• rs291593
• NM_000110.4:c.*780C>T

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.*780C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 152,114 control chromosomes in the GnomAD database, including 6,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6941 hom., cov: 32)
  • Exomes 𝑓: 0.24 (7 hom.)
• Consequence: DPYD NM_000110.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -1.03
• Publications: 16 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

ENSG00000296260 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-97078196-G-A is Benign according to our data. Variant chr1-97078196-G-A is described in ClinVar as Benign. ClinVar VariationId is 100064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.59 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYD	NM_000110.4	c.*780C>T		3_prime_UTR_variant	Exon 23 of 23	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8	c.*780C>T		3_prime_UTR_variant	Exon 23 of 23	1	NM_000110.4	ENSP00000359211.3
ENSG00000296260	ENST00000737657.1	n.550-3551G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.290 AC: 43988 AN: 151798 Hom.: 6936 Cov.: 32

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.608

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.276

GnomAD4 exome AF: 0.237 AC: 47 AN: 198 Hom.: 7 Cov.: 0 AF XY: 0.177 AC XY: 17 AN XY: 96

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.321 AC: 9 AN: 28

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AF: 0.250 AC: 1 AN: 4

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.219 AC: 35 AN: 160

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.290 AC: 44032 AN: 151916 Hom.: 6941 Cov.: 32 AF XY: 0.298 AC XY: 22097 AN XY: 74224

African (AFR) AF: 0.228 AC: 9450 AN: 41452

American (AMR) AF: 0.293 AC: 4471 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 979 AN: 3466

East Asian (EAS) AF: 0.608 AC: 3131 AN: 5152

South Asian (SAS) AF: 0.468 AC: 2253 AN: 4814

European-Finnish (FIN) AF: 0.388 AC: 4084 AN: 10526

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.276 AC: 18721 AN: 67950

Other (OTH) AF: 0.278 AC: 584 AN: 2102

Alfa AF: 0.280 Hom.: 22839

Bravo AF: 0.281

Asia WGS AF: 0.544 AC: 1890 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

-

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

- -

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	-0.90
CADD	Benign	1.2
DANN	Benign	0.24
PhyloP100		-1.0
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: rs291593; hg19: chr1-97543752;