rs759372918
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000110.4(DPYD):c.2275C>T(p.Arg759Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,612,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000110.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DPYD | NM_000110.4 | c.2275C>T | p.Arg759Ter | stop_gained | 18/23 | ENST00000370192.8 | |
DPYD-AS1 | NR_046590.1 | n.129-906G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DPYD | ENST00000370192.8 | c.2275C>T | p.Arg759Ter | stop_gained | 18/23 | 1 | NM_000110.4 | P1 | |
DPYD-AS1 | ENST00000422980.1 | n.129-906G>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000527 AC: 8AN: 151760Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250742Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135500
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1460408Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 726570
GnomAD4 genome ? AF: 0.0000527 AC: 8AN: 151760Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3AN XY: 74104
ClinVar
Submissions by phenotype
Dihydropyrimidine dehydrogenase deficiency Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 05, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 06, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 21, 2023 | Variant summary: DPYD c.2275C>T (p.Arg759X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.8e-05 in 250742 control chromosomes. c.2275C>T has been reported in the literature, however with limited phenotypic information (e.g. Hesse_2018). This report does not provide unequivocal conclusions about association of the variant with Dihydropyrimidine Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 22, 2023 | Reported in a patient with a suspected epilepsy syndrome (Hesse et al., 2018); Nonsense 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: 25087612, 29778030) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 26, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at