Menu
GeneBe

1-97573863-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_StrongBP7BS1BS2

The NM_000110.4(DPYD):c.1236G>A(p.Glu412=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,613,680 control chromosomes in the GnomAD database, including 358 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.013 ( 23 hom., cov: 32)
Exomes 𝑓: 0.019 ( 335 hom. )

Consequence

DPYD
NM_000110.4 synonymous

Scores

2

Clinical Significance

drug response reviewed by expert panel B:5O:3

Conservation

PhyloP100: 0.403
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.32).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-97573863-C-T is Benign according to our data. Variant chr1-97573863-C-T is described in ClinVar as [drug_response]. Clinvar id is 100100.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=4, drug_response=2, not_provided=1, Likely_benign=1}. Variant chr1-97573863-C-T is described in Lovd as [Pathogenic]. Variant chr1-97573863-C-T is described in Lovd as [Benign]. Variant chr1-97573863-C-T is described in Lovd as [Benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.403 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0131 (1993/152190) while in subpopulation NFE AF= 0.0214 (1455/68002). AF 95% confidence interval is 0.0205. There are 23 homozygotes in gnomad4. There are 935 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 23 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DPYDNM_000110.4 linkuse as main transcriptc.1236G>A p.Glu412= synonymous_variant 11/23 ENST00000370192.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DPYDENST00000370192.8 linkuse as main transcriptc.1236G>A p.Glu412= synonymous_variant 11/231 NM_000110.4 P1Q12882-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0131
AC:
1994
AN:
152072
Hom.:
23
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00297
Gnomad AMI
AF:
0.0285
Gnomad AMR
AF:
0.00728
Gnomad ASJ
AF:
0.00547
Gnomad EAS
AF:
0.000578
Gnomad SAS
AF:
0.0161
Gnomad FIN
AF:
0.0142
Gnomad MID
AF:
0.0222
Gnomad NFE
AF:
0.0214
Gnomad OTH
AF:
0.0100
GnomAD3 exomes
AF:
0.0141
AC:
3543
AN:
251150
Hom.:
37
AF XY:
0.0151
AC XY:
2048
AN XY:
135730
show subpopulations
Gnomad AFR exome
AF:
0.00265
Gnomad AMR exome
AF:
0.00449
Gnomad ASJ exome
AF:
0.00665
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0173
Gnomad FIN exome
AF:
0.0122
Gnomad NFE exome
AF:
0.0211
Gnomad OTH exome
AF:
0.0142
GnomAD4 exome
AF:
0.0194
AC:
28307
AN:
1461490
Hom.:
335
Cov.:
31
AF XY:
0.0194
AC XY:
14130
AN XY:
727058
show subpopulations
Gnomad4 AFR exome
AF:
0.00278
Gnomad4 AMR exome
AF:
0.00483
Gnomad4 ASJ exome
AF:
0.00586
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0173
Gnomad4 FIN exome
AF:
0.0133
Gnomad4 NFE exome
AF:
0.0221
Gnomad4 OTH exome
AF:
0.0161
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0131
AC:
1993
AN:
152190
Hom.:
23
Cov.:
32
AF XY:
0.0126
AC XY:
935
AN XY:
74412
show subpopulations
Gnomad4 AFR
AF:
0.00294
Gnomad4 AMR
AF:
0.00727
Gnomad4 ASJ
AF:
0.00547
Gnomad4 EAS
AF:
0.000580
Gnomad4 SAS
AF:
0.0161
Gnomad4 FIN
AF:
0.0142
Gnomad4 NFE
AF:
0.0214
Gnomad4 OTH
AF:
0.00993
Alfa
AF:
0.0180
Hom.:
28
Bravo
AF:
0.0120
Asia WGS
AF:
0.00866
AC:
30
AN:
3478
EpiCase
AF:
0.0183
EpiControl
AF:
0.0191

ClinVar

Significance: drug response
Submissions summary: Benign:5Other:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Benign:2Other:1
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsDec 21, 2017- -
not provided, no classification providedliterature onlyDiasio Lab, Mayo Clinic-- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2024DPYD: BP4, BP7, BS1, BS2 -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 19, 2018Variant summary: DPYD c.1236G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.014 in 276814 control chromosomes in the gnomAD database, including 39 homozygotes. The observed variant frequency is approximately 5.66 fold of the estimated maximal expected allele frequency for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency phenotype (0.0025), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1236G>A in individuals affected with Dihydropyrimidine Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. One other clinical diagnostic laboratory classified this variant as benign via ClinVar. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Dihydropyrimidine dehydrogenase deficiency Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
fluorouracil response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBOct 27, 2022PharmGKB 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
capecitabine response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBOct 26, 2022PharmGKB 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
-0.32
Cadd
Benign
6.8
Dann
Benign
0.54

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: rs56038477; hg19: chr1-98039419; COSMIC: COSV64612239; API