rs57918000
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_000110.4(DPYD):c.1371C>T(p.Asn457=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,613,704 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0072 ( 11 hom., cov: 32)
Exomes 𝑓: 0.00070 ( 14 hom. )
Consequence
DPYD
NM_000110.4 synonymous
NM_000110.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 3.20
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -19 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.42).
BP6
?
Variant 1-97549713-G-A is Benign according to our data. Variant chr1-97549713-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 100097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=3.2 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00716 (1090/152264) while in subpopulation AFR AF= 0.0247 (1025/41544). AF 95% confidence interval is 0.0234. There are 11 homozygotes in gnomad4. There are 518 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 11 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DPYD | NM_000110.4 | c.1371C>T | p.Asn457= | synonymous_variant | 12/23 | ENST00000370192.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DPYD | ENST00000370192.8 | c.1371C>T | p.Asn457= | synonymous_variant | 12/23 | 1 | NM_000110.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00717 AC: 1091AN: 152146Hom.: 11 Cov.: 32
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GnomAD3 exomes AF: 0.00188 AC: 471AN: 250780Hom.: 6 AF XY: 0.00143 AC XY: 194AN XY: 135534
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GnomAD4 exome AF: 0.000700 AC: 1023AN: 1461440Hom.: 14 Cov.: 31 AF XY: 0.000604 AC XY: 439AN XY: 727012
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GnomAD4 genome ? AF: 0.00716 AC: 1090AN: 152264Hom.: 11 Cov.: 32 AF XY: 0.00696 AC XY: 518AN XY: 74452
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2Other:1
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 09, 2018 | - - |
not provided, no classification provided | literature only | Diasio Lab, Mayo Clinic | - | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2019 | - - |
Dihydropyrimidine dehydrogenase deficiency Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 04, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at