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rs67376798

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3BP4_ModerateBS1_SupportingBS2

The NM_000110.4(DPYD):c.2846A>T(p.Asp949Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00504 in 1,613,660 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.0033 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0052 ( 29 hom. )

Consequence

DPYD
NM_000110.4 missense

Scores

10
6
3

Clinical Significance

drug response reviewed by expert panel P:5U:1B:2O:6

Conservation

PhyloP100: 7.82
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 Likely_benign. Variant got -6 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 6: BayesDel_noAF, Eigen, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL [when AlphaMissense, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.13372508).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00328 (499/152236) while in subpopulation NFE AF= 0.00605 (411/67978). AF 95% confidence interval is 0.00556. There are 3 homozygotes in gnomad4. There are 211 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DPYDNM_000110.4 linkuse as main transcriptc.2846A>T p.Asp949Val missense_variant 22/23 ENST00000370192.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DPYDENST00000370192.8 linkuse as main transcriptc.2846A>T p.Asp949Val missense_variant 22/231 NM_000110.4 P1Q12882-1

Frequencies

GnomAD3 genomes
AF:
0.00328
AC:
499
AN:
152118
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00118
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00171
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000621
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00605
Gnomad OTH
AF:
0.00335
GnomAD3 exomes
AF:
0.00285
AC:
715
AN:
251256
Hom.:
0
AF XY:
0.00286
AC XY:
388
AN XY:
135766
show subpopulations
Gnomad AFR exome
AF:
0.000677
Gnomad AMR exome
AF:
0.00260
Gnomad ASJ exome
AF:
0.000397
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000457
Gnomad FIN exome
AF:
0.000324
Gnomad NFE exome
AF:
0.00508
Gnomad OTH exome
AF:
0.00179
GnomAD4 exome
AF:
0.00523
AC:
7640
AN:
1461424
Hom.:
29
Cov.:
33
AF XY:
0.00509
AC XY:
3703
AN XY:
727012
show subpopulations
Gnomad4 AFR exome
AF:
0.00105
Gnomad4 AMR exome
AF:
0.00235
Gnomad4 ASJ exome
AF:
0.000268
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000522
Gnomad4 FIN exome
AF:
0.000487
Gnomad4 NFE exome
AF:
0.00645
Gnomad4 OTH exome
AF:
0.00409
GnomAD4 genome
AF:
0.00328
AC:
499
AN:
152236
Hom.:
3
Cov.:
32
AF XY:
0.00283
AC XY:
211
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.00118
Gnomad4 AMR
AF:
0.00170
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000622
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.00605
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.00517
Hom.:
1
Bravo
AF:
0.00345
TwinsUK
AF:
0.00890
AC:
33
ALSPAC
AF:
0.00493
AC:
19
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00547
AC:
47
ExAC
AF:
0.00263
AC:
319
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00524
EpiControl
AF:
0.00492

ClinVar

Significance: drug response
Submissions summary: Pathogenic:5Uncertain:1Benign:2Other:6
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 04, 2021Variant summary: DPYD c.2846A>T (p.Asp949Val) results in a non-conservative amino acid change located in the 4Fe-4S ferredoxin-type, iron-sulphur binding domain (IPR017896) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 251256 control chromosomes (gnomAD). The observed variant frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency phenotype (0.0025). c.2846A>T has been reported in the literature in multiple individuals affected with Dihydropyrimidine Dehydrogenase Deficiency (e.g. van Kuilenburg_2002 and 2016, Henricks_2017, Pallet_2020). In addition, the variant was reported to be associated with lower DPD enzyme activity, reduced 5-fluorouracil clearances and increased risk of fluoropyrimidine-induced toxicity in heterozygous individuals (e.g. Caudle 2013, Henricks_2015, Madi 2018, Lunenburg_2020). Several Pharmacogenetics groups, including the Dutch Pharmacogenetics Working Group (DPWG), the Swiss Group of Pharmacogenomics and Personalised Therapy and the Clinical Pharmacogenetics Implementation Consortium (CPIC), recently released guidelines documenting c.2846A>T to be associated with moderately reduced DPD activity and strongly recommending DPYD genotyping of this and a few other variants prior to the start of therapy with fluoropyrimidines in cancer patients, followed by a reduction of the initial standard dose in genotyped-positive patients in order to decrease the risk of fluoropyrimidine-induced toxicity (Amstutz_2018, Hamzic_2020, Lunenburg_2020). Experimental evidence evaluating an impact on protein function demonstrated the variant to result in decreased enzyme activity (e.g. van Kuilenburg_2002, Offer_2014, van Kuilenburg_2016, Henricks_2017). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1), as likely pathogenic (n=1) and as uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteFeb 02, 2022Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene and is associated with dihydropyrimidine dehydrogenase deficiency (MIM#274270). (I) 0106 - This gene is known to be associated with autosomal recessive disease. However, heterozygous carriers of some variants may also show a reduction in dihydropyrimidine dehydrogenase activity and can present 5-fluorouracil toxicity (PMID: 29152729, 26265346). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to valine. (I) 0251 - Variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 815 heterozygotes, 1 homozygote; v3: 493 heterozygotes, 3 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in an annotated domain or motif (4Fe-4S dicluster domain; NCBI). (I) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in patients with dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity (ClinVar, PMID: 11988088, 26804652, 30510603, 32595208). (SP) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies show that this variant reduces enzyme activity (PMID: 26804652, 24648345). (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitterclinical testingCounsylApr 20, 2016- -
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics, Royal Melbourne HospitalMar 01, 2024This sequence change in DPYD is predicted to replace aspartic acid with valine at codon 949, p.(Asp949Val). The aspartic acid residue is highly conserved (100 vertebrates, Multiz alignments), and is located in the 4Fe-4S ferredoxin-type 2 domain. There is a large physicochemical difference between aspartic acid and valine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.6% (7,583/1,179,644 alleles, 29 homozygotes) in the European (non-Finnish) population. The variant is significantly associated with severe fluoropyrimidine-associated toxicity and is an annotated drug response allele with recommendations for fluoropyrimidine dosing (PMID: 26603945, 29152729, 24648345). It has been detected compound heterozygous with a second pathogenic variant in at least six individuals with dihydropyrimidine dehydrogenase (DPD) deficiency and/or severe fluoropyrimidine-related toxicity (PMID: 11988088, 17064846, 25381393, 26804652, 31124962, 32595208). Multiple individuals with this variant displayed loss/strongly decreased DPD enzyme activity and increased Uracil and Thymine plasma levels, which is highly specific for DPD deficiency (PMID: 11988088, 17064846, 26804652, 32595208). DPD enzyme activity assays in cell lines showed partially reduced activity indicating that this variant impacts protein function (PMID: 24648345, 26804652). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.962). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PM3_Strong, PS3_Supporting, PP3_Moderate, PP4, BS1. -
not provided Pathogenic:1Benign:1Other:1
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2023DPYD: PS3:Very Strong, PM2 -
not provided, no classification providedliterature onlyDiasio Lab, Mayo Clinic-- -
Benign, criteria provided, single submitterclinical testingGeneDxAug 20, 2020Individuals who carry at least one DPYD D949V allele are at risk to experience drug toxicity when treated with fluoropyrimidine drugs. Dosing guidelines based on DPYD genotype are available (Amstutz et al., 2018); Published functional studies demonstrate decreased enzymatic activity for D949V (Kuilenburg et al., 2016; Offer et al., 2014); This variant is associated with the following publications: (PMID: 32595208, 31980526, 29152729, 10071185, 15377401, 17700593, 18299612, 19104657, 19296131, 19473056, 20819423, 21077799, 23736036, 23930673, 24167597, 24590654, 24648345, 25381393, 25410891, 24647007, 24923815, 25677447, 26099996, 26265346, 26216193, 27454530, 28295243, 28427087, 28481884, 29065426, 30114658, 21228398, 22995991, 31124962, 30609409, 11156223, 17064846, 17121937, 23988873, 26265035, 26804652, 16115930, 11875367, 27995989, 26794347, 30510603, 26603945, 23603345, 21498394, 21410976, 19795123, 11988088) -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 08, 2016- -
DPYD-related condition Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesDec 15, 2023This 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). -
tegafur response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMay 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
fluorouracil response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMay 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
fluorouracil response - Other Other:1
drug response, reviewed by expert panelcurationPharmGKBMay 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: Other
capecitabine response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMay 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
Fluorouracil response Other:1
other, no assertion criteria providedclinical testingGenetic Services Laboratory, University of ChicagoFeb 29, 2016- Reduced function allele

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Pathogenic
0.46
Cadd
Uncertain
25
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.43
T
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.35
D
MetaRNN
Benign
0.13
T
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.1
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-7.2
D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.95
MVP
0.94
MPC
0.22
ClinPred
0.054
T
GERP RS
5.8
Varity_R
0.75
gMVP
0.94

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: rs67376798; hg19: chr1-97547947; COSMIC: COSV100929857; API