chr1-97740410-GATGA-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000110.4(DPYD):c.299_302delTCAT(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
Consequence
NM_000110.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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DPYD | ENST00000370192.8 | c.299_302delTCAT | p.Phe100SerfsTer15 | frameshift_variant | Exon 4 of 23 | 1 | NM_000110.4 | ENSP00000359211.3 | ||
DPYD | ENST00000306031.5 | c.299_302delTCAT | p.Phe100SerfsTer15 | frameshift_variant | Exon 4 of 6 | 1 | ENSP00000307107.5 |
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152088Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000104 AC: 26AN: 251156Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135738
GnomAD4 exome AF: 0.000114 AC: 166AN: 1460428Hom.: 0 AF XY: 0.000113 AC XY: 82AN XY: 726592
GnomAD4 genome AF: 0.000118 AC: 18AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74408
ClinVar
Submissions by phenotype
Dihydropyrimidine dehydrogenase deficiency Pathogenic:5
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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." -
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not provided Pathogenic:1
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: 34697415, 10071185, 9254861, 19296131, 31589614) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at