rs67376798
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3BP4_ModerateBS1_SupportingBS2
The NM_000110(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 0.00328 in 152118 control chromosomes in the gnomAD Genomes database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (β β β ).
Frequency
Genomes: π 0.0033 ( 3 hom., cov: 32)
Exomes π: 0.0028 ( 0 hom. )
Consequence
DPYD
NM_000110 missense
NM_000110 missense
Scores
10
6
3
Clinical Significance
Conservation
PhyloP100: 7.82
Links
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. gnomad allele frequency = 0.00328 (499/152118) while in subpopulation NFE AF= 0.00605 (411/67986). AF 95% confidence interval is 0.00556. There are 3 homozygotes in gnomad. There are 211 alleles in male gnomad subpopulation. Median coverage is 32. 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 |
---|---|---|---|---|---|---|---|
DPYD | NM_000110.4 | c.2846A>T | p.Asp949Val | missense_variant | 22/23 | ENST00000370192.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DPYD | ENST00000370192.8 | c.2846A>T | p.Asp949Val | missense_variant | 22/23 | 1 | NM_000110.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00328 AC: 499AN: 152118Hom.: 3 Cov.: 32
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GnomAD3 exomes AF: 0.00285 AC: 715AN: 251256Hom.: 0 AF XY: 0.00286 AC XY: 388AN XY: 135766
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ClinVar
Significance: drug response
Submissions summary: Pathogenic:4Uncertain:2Benign:1Other:6
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Dihydropyrimidine dehydrogenase deficiency Pathogenic:3Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 20, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 04, 2021 | Variant 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 submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based 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 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided Pathogenic:1Benign:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2020 | - - |
not provided, no assertion provided | literature only | Diasio Lab, Mayo Clinic | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 20, 2020 | Individuals 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 submitter | clinical testing | Ambry Genetics | Nov 08, 2016 | - - |
tegafur response - Toxicity Other:1
drug response, reviewed by expert panel | curation | PharmGKB | May 24, 2021 | PharmGKB 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 panel | curation | PharmGKB | May 24, 2021 | PharmGKB 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 panel | curation | PharmGKB | May 24, 2021 | PharmGKB 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 panel | curation | PharmGKB | May 24, 2021 | PharmGKB 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 provided | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 29, 2016 | - Reduced function allele |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at