ENST00000646851.1:n.688+20408G>A

Variant names:

• chr1-97921165-C-T
• rs72981743
• ENST00000646851.1:n.688+20408G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000646851.1(DPYD):​n.688+20408G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0979 in 209,542 control chromosomes in the GnomAD database, including 1,180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.10 (919 hom., cov: 31)
  • Exomes 𝑓: 0.085 (261 hom.)
• Consequence: DPYD ENST00000646851.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.14
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-97921165-C-T is Benign according to our data. Variant chr1-97921165-C-T is described in ClinVar as Benign. ClinVar VariationId is 1266319.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000646851.1. 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.-243G>A		upstream_gene	N/A	NP_000101.2
	DPYD	NM_001160301.1		c.-243G>A		upstream_gene	N/A	NP_001153773.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYD	ENST00000646851.1		n.688+20408G>A		intron	N/A
	DPYD	ENST00000370192.8	TSL:1 MANE Select	c.-243G>A		upstream_gene	N/A	ENSP00000359211.3
	DPYD	ENST00000306031.5	TSL:1	c.-243G>A		upstream_gene	N/A	ENSP00000307107.5

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15562 AN: 151438 Hom.: 919 Cov.: 31

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0585

Gnomad EAS AF: 0.00845

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.0837

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0860

Gnomad OTH AF: 0.102

GnomAD4 exome AF: 0.0849 AC: 4925 AN: 57994 Hom.: 261 AF XY: 0.0842 AC XY: 2759 AN XY: 32770

African (AFR) AF: 0.138 AC: 187 AN: 1354

American (AMR) AF: 0.134 AC: 209 AN: 1558

Ashkenazi Jewish (ASJ) AF: 0.0750 AC: 110 AN: 1466

East Asian (EAS) AF: 0.00583 AC: 17 AN: 2914

South Asian (SAS) AF: 0.134 AC: 102 AN: 760

European-Finnish (FIN) AF: 0.0842 AC: 451 AN: 5354

Middle Eastern (MID) AF: 0.108 AC: 31 AN: 288

European-Non Finnish (NFE) AF: 0.0861 AC: 3518 AN: 40836

Other (OTH) AF: 0.0866 AC: 300 AN: 3464

GnomAD4 genome AF: 0.103 AC: 15579 AN: 151548 Hom.: 919 Cov.: 31 AF XY: 0.104 AC XY: 7734 AN XY: 74034

African (AFR) AF: 0.131 AC: 5442 AN: 41398

American (AMR) AF: 0.146 AC: 2222 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.0585 AC: 203 AN: 3468

East Asian (EAS) AF: 0.00847 AC: 43 AN: 5076

South Asian (SAS) AF: 0.127 AC: 611 AN: 4814

European-Finnish (FIN) AF: 0.0837 AC: 876 AN: 10470

Middle Eastern (MID) AF: 0.106 AC: 31 AN: 292

European-Non Finnish (NFE) AF: 0.0860 AC: 5832 AN: 67790

Other (OTH) AF: 0.100 AC: 211 AN: 2100

Alfa AF: 0.0522 Hom.: 58

Bravo AF: 0.106

Asia WGS AF: 0.0650 AC: 228 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.7
DANN	Benign	0.91
PhyloP100		-2.1
PromoterAI		-0.025	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72981743; hg19: chr1-98386721;