1-97078196-G-A

Position:

• chr1-97078196-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
DPYD	NM_000110.4	c.*780C>T		3_prime_UTR_variant	23/23	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192	c.*780C>T		3_prime_UTR_variant	23/23	1	NM_000110.4	ENSP00000359211.3

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

Gnomad4 AMR exome AF: 0.321

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.250

Gnomad4 NFE exome AF: 0.219

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.228

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.282

Gnomad4 EAS AF: 0.608

Gnomad4 SAS AF: 0.468

Gnomad4 FIN AF: 0.388

Gnomad4 NFE AF: 0.276

Gnomad4 OTH AF: 0.278

Alfa AF: 0.278 Hom.: 9391

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

not provided, no classification provided	literature only	Diasio Lab, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Dihydropyrimidine dehydrogenase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

LitVar

Other links and lift over

dbSNP: rs291593; hg19: chr1-97543752;