rs1057516968
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000110.4(DPYD):c.1681C>T(p.Arg561Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000744 in 1,612,732 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R561R) has been classified as Likely benign. 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.1681C>T | p.Arg561Ter | stop_gained | 13/23 | ENST00000370192.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DPYD | ENST00000370192.8 | c.1681C>T | p.Arg561Ter | stop_gained | 13/23 | 1 | NM_000110.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 151914Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250608Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135404
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460818Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726736
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 151914Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74180
ClinVar
Submissions by phenotype
Dihydropyrimidine dehydrogenase deficiency Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 23, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 14, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 11, 2023 | - - |
DPYD-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 05, 2023 | The DPYD c.1681C>T variant is predicted to result in premature protein termination (p.Arg561*). This variant was reported along with another variant in DPYD, in an individual with colon cancer experiencing severe grade IV toxicity (van Kuilenburg et al. 2016. PubMed ID: 26804652). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-97981341-G-A). Nonsense variants in DPYD are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 03, 2018 | The R561X variant has beenreported previously, along with a second DPYD variant, in an individual with colon cancer with severe grade IV toxicity to 5-FU (van Kuilenburg et al., 2016). Functional studies indicate that R561X impairs DPD enzyme activity (van Kuilenburg et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.Furthermore, the R561X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at