GeneBe

rs17376848

Positions:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_StrongBP7BA1

The NM_000110.4(DPYD):​c.1896T>C​(p.Phe632=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0466 in 1,613,826 control chromosomes in the GnomAD database, including 2,196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.044 ( 194 hom., cov: 32)
Exomes 𝑓: 0.047 ( 2002 hom. )

Consequence

DPYD
NM_000110.4 synonymous

Scores

2

Clinical Significance

drug response reviewed by expert panel B:2O:3

Conservation

PhyloP100: 0.288
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.65).
BP6
Variant 1-97450068-A-G is Benign according to our data. Variant chr1-97450068-A-G is described in ClinVar as [drug_response]. Clinvar id is 100088.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Benign=2, drug_response=2}. Variant chr1-97450068-A-G is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.288 with no splicing effect.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DPYDNM_000110.4 linkuse as main transcriptc.1896T>C p.Phe632= synonymous_variant 14/23 ENST00000370192.8 NP_000101.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DPYDENST00000370192.8 linkuse as main transcriptc.1896T>C p.Phe632= synonymous_variant 14/231 NM_000110.4 ENSP00000359211 P1Q12882-1

Frequencies

GnomAD3 genomes
AF:
0.0438
AC:
6666
AN:
152132
Hom.:
195
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0216
Gnomad AMI
AF:
0.126
Gnomad AMR
AF:
0.0729
Gnomad ASJ
AF:
0.0130
Gnomad EAS
AF:
0.124
Gnomad SAS
AF:
0.0391
Gnomad FIN
AF:
0.0483
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0452
Gnomad OTH
AF:
0.0388
GnomAD3 exomes
AF:
0.0510
AC:
12816
AN:
251280
Hom.:
454
AF XY:
0.0490
AC XY:
6653
AN XY:
135808
show subpopulations
Gnomad AFR exome
AF:
0.0218
Gnomad AMR exome
AF:
0.0873
Gnomad ASJ exome
AF:
0.0101
Gnomad EAS exome
AF:
0.126
Gnomad SAS exome
AF:
0.0347
Gnomad FIN exome
AF:
0.0480
Gnomad NFE exome
AF:
0.0411
Gnomad OTH exome
AF:
0.0421
GnomAD4 exome
AF:
0.0469
AC:
68503
AN:
1461576
Hom.:
2002
Cov.:
31
AF XY:
0.0458
AC XY:
33324
AN XY:
727076
show subpopulations
Gnomad4 AFR exome
AF:
0.0183
Gnomad4 AMR exome
AF:
0.0853
Gnomad4 ASJ exome
AF:
0.00991
Gnomad4 EAS exome
AF:
0.131
Gnomad4 SAS exome
AF:
0.0346
Gnomad4 FIN exome
AF:
0.0450
Gnomad4 NFE exome
AF:
0.0453
Gnomad4 OTH exome
AF:
0.0468
GnomAD4 genome
AF:
0.0438
AC:
6664
AN:
152250
Hom.:
194
Cov.:
32
AF XY:
0.0452
AC XY:
3366
AN XY:
74444
show subpopulations
Gnomad4 AFR
AF:
0.0215
Gnomad4 AMR
AF:
0.0727
Gnomad4 ASJ
AF:
0.0130
Gnomad4 EAS
AF:
0.124
Gnomad4 SAS
AF:
0.0387
Gnomad4 FIN
AF:
0.0483
Gnomad4 NFE
AF:
0.0452
Gnomad4 OTH
AF:
0.0393
Alfa
AF:
0.0417
Hom.:
321
Bravo
AF:
0.0446
Asia WGS
AF:
0.0850
AC:
296
AN:
3478

ClinVar

Significance: drug response
Submissions summary: Benign:2Other:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Dihydropyrimidine dehydrogenase deficiency Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
fluorouracil response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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: Toxicity
not provided Other:1
not provided, no classification providedliterature onlyDiasio Lab, Mayo Clinic-- -
capecitabine response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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: Toxicity

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.65
CADD
Benign
3.1
DANN
Benign
0.61

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs17376848; hg19: chr1-97915624; COSMIC: COSV100928729; API