rs67376798
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_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
Consequence
NM_000110.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00328 AC: 499AN: 152118Hom.: 3 Cov.: 32
GnomAD3 exomes AF: 0.00285 AC: 715AN: 251256Hom.: 0 AF XY: 0.00286 AC XY: 388AN XY: 135766
GnomAD4 exome AF: 0.00523 AC: 7640AN: 1461424Hom.: 29 Cov.: 33 AF XY: 0.00509 AC XY: 3703AN XY: 727012
GnomAD4 genome 0.00328 AC: 499AN: 152236Hom.: 3 Cov.: 32 AF XY: 0.00283 AC XY: 211AN XY: 74456
ClinVar
Submissions by phenotype
Dihydropyrimidine dehydrogenase deficiency Pathogenic:5
This 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. -
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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). The following publications have been ascertained in the context of this evaluation (PMID: 29152729, 23988873, 30510603, 33232506, 26265346, 31745289, 30114658, 24648345, 32595208, 16115930, 26804652, 11988088, 11156223). ClinVar contains an entry for this variant (Variation ID: 88974). Based on the evidence outlined above, the variant was classified as pathogenic. -
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 -
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not provided Pathogenic:1Benign:2Other:1
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 (PMID: 29152729); Published functional studies demonstrate decreased enzymatic activity for D949V (PMID: 26804652, 24648345); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11156223, 34697415, 27995989, 26794347, 30510603, 26603945, 23603345, 21498394, 21410976, 19795123, 11988088, 11875367, 16115930, 23988873, 26265035, 17121937, 17064846, 30609409, 31124962, 22995991, 21228398, 30114658, 29065426, 28481884, 28427087, 28295243, 27454530, 26216193, 26265346, 26099996, 25677447, 24923815, 24647007, 25410891, 25381393, 24648345, 24590654, 24167597, 23930673, 23736036, 21077799, 20819423, 19473056, 19296131, 19104657, 18299612, 17700593, 15377401, 10071185, 31980526, 34426522, 32595208, 26804652, 29152729) -
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DPYD: PS3:Very Strong, PM2 -
DPYD-related disorder Pathogenic:1
PS3, PS4, PP3, BS1 -
Inborn genetic diseases Uncertain:1
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tegafur response - Toxicity Other:1
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
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
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
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
- Reduced function allele
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at