rs72549309

chr1-97740410-GATGA-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000110.4(DPYD):c.299_302del(p.Phe100SerfsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,612,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: DPYD NM_000110.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.65

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-97740410-GATGA-G is Pathogenic according to our data. Variant chr1-97740410-GATGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 495550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-97740410-GATGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPYD	NM_000110.4	c.299_302del	p.Phe100SerfsTer15	frameshift_variant	4/23	ENST00000370192.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPYD	ENST00000370192.8	c.299_302del	p.Phe100SerfsTer15	frameshift_variant	4/23	1	NM_000110.4	P1
DPYD	ENST00000306031.5	c.299_302del	p.Phe100SerfsTer15	frameshift_variant	4/6	1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000104 AC: 26 AN: 251156 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000114 AC: 166 AN: 1460428 Hom.: 0 AF XY: 0.000113 AC XY: 82 AN XY: 726592

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74408

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000491

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 06, 2017	Variant summary: The DPYD c.299_302delTCAT (p.Phe100Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent DPYD protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 11/121318 control chromosomes at a frequency of 0.0000907, which does not exceed the estimated maximal expected allele frequency of a pathogenic DPYD variant (0.0025). Multiple publications have cited the variant in homozygous and compound heterozygous affected individuals. Vreken_1997 reports the variant in one family, 3 homozygous individuals, the proband presented at the age of 4, while the mother didn't present until age of 19 with generalized tonic seizures. The brother, who was also homozygous for the variant was indicated to be normal, although the age of the brother was not provided. All three individuals were found to have no detectable levels of DPD activity. The variant of interest has not, to our knowledge, been cited and classified by other clinical diagnostic laboratories or reputable databases (other than HGMD). Therefore, the variant of interest has been classified as "pathogenic." -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 12, 2022

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 9254861, 10071185, 19296131, 31589614) -

Computational scores

Source: dbNSFP v4.3

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: rs72549309; hg19: chr1-98205966;