rs121964924
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001385.3(DPYS):āc.1078T>Cā(p.Trp360Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,194 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 (ā ā ).
Frequency
Genomes: š 0.000053 ( 0 hom., cov: 31)
Exomes š: 0.000031 ( 0 hom. )
Consequence
DPYS
NM_001385.3 missense
NM_001385.3 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 9.32
Genes affected
DPYS (HGNC:3013): (dihydropyrimidinase) Dihydropyrimidinase catalyzes the conversion of 5,6-dihydrouracil to 3-ureidopropionate in pyrimidine metabolism. Dihydropyrimidinase is expressed at a high level in liver and kidney as a major 2.5-kb transcript and a minor 3.8-kb transcript. Defects in the DPYS gene are linked to dihydropyrimidinuria. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.983
PP5
?
Variant 8-104427994-A-G is Pathogenic according to our data. Variant chr8-104427994-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DPYS | NM_001385.3 | c.1078T>C | p.Trp360Arg | missense_variant | 6/10 | ENST00000351513.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DPYS | ENST00000351513.7 | c.1078T>C | p.Trp360Arg | missense_variant | 6/10 | 1 | NM_001385.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152218Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251460Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135898
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GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461858Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25AN XY: 727238
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GnomAD4 genome ? AF: 0.0000525 AC: 8AN: 152336Hom.: 0 Cov.: 31 AF XY: 0.0000671 AC XY: 5AN XY: 74492
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Dihydropyrimidinase deficiency Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1998 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 360 of the DPYS protein (p.Trp360Arg). This variant is present in population databases (rs121964924, gnomAD 0.02%). This missense change has been observed in individual(s) with dihydropyrimidinuria (PMID: 17383919, 20362666). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 186). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DPYS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DPYS function (PMID: 17383919, 20362666, 28642038). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 09, 2021 | Published functional studies demonstrate impaired enzymatic activity due to possible conformation changes leading to protein misfolding and instability (Hamajima et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9266350, 9718352, 28642038, 19649633, 27063261, 17383919, 18600547, 20362666, 31589614, 31980526, 30409984, 32707991) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.0019);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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