chr1-97234991-G-T
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_000110.4(DPYD):c.2303C>A(p.Thr768Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000355 in 1,613,978 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).
Frequency
Consequence
NM_000110.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DPYD | NM_000110.4 | c.2303C>A | p.Thr768Lys | missense_variant | 19/23 | ENST00000370192.8 | NP_000101.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DPYD | ENST00000370192.8 | c.2303C>A | p.Thr768Lys | missense_variant | 19/23 | 1 | NM_000110.4 | ENSP00000359211.3 | ||
DPYD-AS1 | ENST00000422980.1 | n.65-30423G>T | intron_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.000204 AC: 31AN: 152060Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000211 AC: 53AN: 251018Hom.: 0 AF XY: 0.000221 AC XY: 30AN XY: 135662
GnomAD4 exome AF: 0.000371 AC: 542AN: 1461800Hom.: 4 Cov.: 33 AF XY: 0.000370 AC XY: 269AN XY: 727198
GnomAD4 genome AF: 0.000204 AC: 31AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74410
ClinVar
Submissions by phenotype
Dihydropyrimidine dehydrogenase deficiency Uncertain:1Benign:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Dec 15, 2017 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 02, 2020 | Identified with a second missense variant, phase unknown, in a female Japanese individual with very low dihydropyrimidine dehydrogenase (DPD) activity and protein expression levels (Ogura et al., 2005); Functional studies are discordant in their conclusions regarding enzyme activity (Offer et al., 2014; Ogura et al., 2005); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in the heterozygous state in 3-6% of Japanese individuals (Maekawa et al., 2007; Okamoto et al., 2007); This variant is associated with the following publications: (PMID: 29769267, 20920994, 17876700, 19287123, 17828463, 24163242, 21498394, 16033824, 24648345, 32619063, 32707991) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 14, 2016 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 02, 2021 | The c.2303C>A (p.T768K) alteration is located in exon 19 (coding exon 19) of the DPYD gene. This alteration results from a C to A substitution at nucleotide position 2303, causing the threonine (T) at amino acid position 768 to be replaced by a lysine (K). The in silico prediction for the p.T768K alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
DPYD-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 13, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
fluorouracil response - Other Other:1
drug response, reviewed by expert panel | curation | PharmGKB | May 25, 2021 | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Other |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at