rs1801267

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_000110.4(DPYD):​c.2657G>T​(p.Arg886Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R886H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DPYD
NM_000110.4 missense

Scores

6
12
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.85
Variant links:
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]
DPYD-AS1 (HGNC:40195): (DPYD antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-97098598-C-T is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DPYDNM_000110.4 linkc.2657G>T p.Arg886Leu missense_variant Exon 21 of 23 ENST00000370192.8 NP_000101.2 Q12882-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DPYDENST00000370192.8 linkc.2657G>T p.Arg886Leu missense_variant Exon 21 of 23 1 NM_000110.4 ENSP00000359211.3 Q12882-1
DPYD-AS1ENST00000422980.1 linkn.64+2612C>A intron_variant Intron 1 of 4 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460840
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726720
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Uncertain
0.13
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.55
D
Eigen
Uncertain
0.68
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.91
D
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.86
D
MetaSVM
Uncertain
0.74
D
MutationAssessor
Pathogenic
3.1
M
PrimateAI
Uncertain
0.56
T
PROVEAN
Pathogenic
-4.8
D
REVEL
Pathogenic
0.75
Sift
Uncertain
0.0060
D
Sift4G
Uncertain
0.0050
D
Polyphen
1.0
D
Vest4
0.73
MutPred
0.55
Loss of sheet (P = 0.0104);
MVP
0.97
MPC
0.37
ClinPred
1.0
D
GERP RS
4.8
Varity_R
0.37
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-97564154; API