NM_000110.4:c.1905+1G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PVS1_ModeratePP5_StrongBS1_Supporting

The NM_000110.4(DPYD):​c.1905+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00506 in 1,613,786 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as drug response (β˜…β˜…β˜…).

Frequency

Genomes: 𝑓 0.0046 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0051 ( 38 hom. )

Consequence

DPYD
NM_000110.4 splice_donor, intron

Scores

4
2
1
Splicing: ADA: 0.9999
2

Clinical Significance

drug response reviewed by expert panel P:19U:1B:1O:6

Conservation

PhyloP100: 7.57
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 Uncertain_significance. Variant got 5 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05360624 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PP5
Variant 1-97450058-C-T is Pathogenic according to our data. Variant chr1-97450058-C-T is described in ClinVar as [drug_response]. Clinvar id is 432.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Benign=1, drug_response=4, Pathogenic=16, Likely_pathogenic=1, not_provided=2}. Variant chr1-97450058-C-T is described in Lovd as [Pathogenic]. Variant chr1-97450058-C-T is described in Lovd as [Pathogenic]. Variant chr1-97450058-C-T is described in Lovd as [Benign]. Variant chr1-97450058-C-T is described in Lovd as [Likely_pathogenic].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00456 (694/152272) while in subpopulation NFE AF= 0.005 (340/68028). AF 95% confidence interval is 0.00456. There are 3 homozygotes in gnomad4. There are 417 alleles in male gnomad4 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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DPYDNM_000110.4 linkc.1905+1G>A splice_donor_variant, intron_variant Intron 14 of 22 ENST00000370192.8 NP_000101.2 Q12882-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DPYDENST00000370192.8 linkc.1905+1G>A splice_donor_variant, intron_variant Intron 14 of 22 1 NM_000110.4 ENSP00000359211.3 Q12882-1

Frequencies

GnomAD3 genomes
AF:
0.00455
AC:
693
AN:
152154
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000579
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00170
Gnomad ASJ
AF:
0.00691
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00269
Gnomad FIN
AF:
0.0243
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00500
Gnomad OTH
AF:
0.00383
GnomAD3 exomes
AF:
0.00559
AC:
1405
AN:
251260
Hom.:
9
AF XY:
0.00580
AC XY:
788
AN XY:
135812
show subpopulations
Gnomad AFR exome
AF:
0.000677
Gnomad AMR exome
AF:
0.00113
Gnomad ASJ exome
AF:
0.00506
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00431
Gnomad FIN exome
AF:
0.0242
Gnomad NFE exome
AF:
0.00547
Gnomad OTH exome
AF:
0.00441
GnomAD4 exome
AF:
0.00511
AC:
7473
AN:
1461514
Hom.:
38
Cov.:
30
AF XY:
0.00503
AC XY:
3658
AN XY:
727052
show subpopulations
Gnomad4 AFR exome
AF:
0.000359
Gnomad4 AMR exome
AF:
0.00114
Gnomad4 ASJ exome
AF:
0.00540
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00406
Gnomad4 FIN exome
AF:
0.0231
Gnomad4 NFE exome
AF:
0.00482
Gnomad4 OTH exome
AF:
0.00505
GnomAD4 genome
AF:
0.00456
AC:
694
AN:
152272
Hom.:
3
Cov.:
32
AF XY:
0.00560
AC XY:
417
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.000578
Gnomad4 AMR
AF:
0.00170
Gnomad4 ASJ
AF:
0.00691
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00290
Gnomad4 FIN
AF:
0.0243
Gnomad4 NFE
AF:
0.00500
Gnomad4 OTH
AF:
0.00379
Alfa
AF:
0.00424
Hom.:
6
Bravo
AF:
0.00274
TwinsUK
AF:
0.00431
AC:
16
ALSPAC
AF:
0.00519
AC:
20
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00581
AC:
50
ExAC
AF:
0.00522
AC:
634
Asia WGS
AF:
0.00260
AC:
9
AN:
3478

ClinVar

Significance: drug response
Submissions summary: Pathogenic:19Uncertain:1Benign:1Other:6
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency Pathogenic:9Other:1
Nov 01, 2021
Centogene AG - the Rare Disease Company
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 24, 2016
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Across a selection of available literature, the c.1905+1G>A variant has been reported in at least 30 patients with dihydropyrimidine dehydrogenase deficiency, including in at least four patients in a homozygous state and in 26 patients in a heterozygous state, all of whom had 5-fluorouracil (5-FU) toxicity (Vreken et al. 1996; Van Kuilenburg et al. 1999; Van Kuilenburg et al. 2002; Morel et al. 2006; Magne et al. 2007). The c.1905+1G>A variant was found in one of 74 controls and is reported at a frequency of 0.02209 in the European (Finnish) population of the Exome Aggregation Consortium. The DPYD c.1905+1G>A variant occurs in a canonical splice site (donor) and results in skipping of exon 14 leading to an inactive DPYD allele (Wei et al. 1996). In patients with the c.1905+1G>A variant in a heterozygous state, conversion of 5-FU was shown to be 40% lower compared to controls (Van Kuilenburg et al. 2012). Based on the collective evidence, the c.1905+1G>A variant is classified as pathogenic for dihydropyrimidine dehydrogenase deficiency. -

Jan 18, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
GenomeConnect - Brain Gene Registry
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 01-14-2020 by Lab PreventionGenetics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Mar 30, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 17, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Jan 03, 2022
3billion, Medical Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000000432, 3billion dataset).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 01, 1999
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

May 06, 2021
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 in this gene and is associated with dihydropyrimidine dehydrogenase deficiency (MIM#274270). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Asymptomatic individuals with biallelic variants are well reported (OMIM). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR on patient cell-derived RNA demonstrates that this variant results in exon 14 skipping. This results in an inframe deletion, and the protein product p.(Asp581_Asn635del) (PMID: 8892022). (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v2) >=0.01 and <0.03 for a recessive condition (1590 heterozygotes, 9 homozygotes). (I) 0311 - An alternative nucleotide change at the same canonical splice site is present in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in homozygous and compound heterozygous patients with dihydropyrimidine dehydrogenase deficiency (ClinVar, PMID: 8892022, PMID: 28929491). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Patient fibroblasts homozygous for this variant have been shown with no detectable enzyme activity (PMID: 8892022). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:5Benign:1Other:1
Jun 01, 2015
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 23, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 31, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Individuals who carry at least one DPYD c.1905+1G>A 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 variant results in a nonfunctional DPYD protein (Offer et al., 2013); This variant is associated with the following publications: (PMID: 24700034, 19178088, 25525159, 11895907, 8892022, 12668826, 22975760, 25906475, 25087612, 22339448, 21114665, 15093568, 19473056, 26804652, 25590979, 26559152, 26603945, 30609409, 31124962, 30775324, 31980526, 33326653, 30755392, 32595208, 33877893, 23328581, 34426522, 34026625, 29152729, 34697415) -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

DPYD: PM3:Strong, PP4:Moderate, PS3:Moderate, PVS1:Moderate, PM2:Supporting -

Jul 09, 2019
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. The best available variant frequency is more than 10 times the disease allele frequency. Damaging to protein function(s) relevant to disease mechanism. Strong co-segregation with disease, and data include affected and unaffected individuals from multiple families -

-
Diasio Lab, Mayo Clinic
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

May 11, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Fluorouracil response Pathogenic:2
Jan 01, 1999
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

May 04, 2016
Genetic Services Laboratory, University of Chicago
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

DPYD-related disorder Pathogenic:1
Jan 01, 2024
Daryl Scott Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1, PS3 -

Inborn genetic diseases Pathogenic:1
Mar 09, 2021
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1905+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 14 of the DPYD gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the DPYD c.1905+1G>A alteration was observed in 0.57% (1608/282660) of total alleles studied including 9 homozygotes, with a frequency of 2.38% (599/25120) in the European (Finnish) subpopulation. This alteration (also referred to as DYPD*2A) has been reported in the homozygous and compound heterozygous states in patients with DPD deficiency and variable phenotypes including neurological disorders and 5-fluorouracil toxicity (Vreken, 1996; Johnson, 2002; Zhu, 2015). This nucleotide position is highly conserved in available vertebrate species. Functional studies demonstrate that this alteration results in exon 14 skipping, undetectable enzyme activity and inability to convert 5-FU to DHFU leading to 5-florouracil toxicity (Vreken, 1996; Johnson, 2002; Offer, 2013). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

Aggressive behavior;C0004352:Autism;C0018536:Hallux valgus;C0024421:Macroglossia;C0036572:Seizure;C0221354:Frontal bossing;C0240543:Bulbous nose;C0338656:Cognitive impairment;C0399526:Mandibular prognathia;C0557874:Global developmental delay;C1836195:Short toe;C1839739:Thick lower lip vermilion;C1844813:Widely spaced teeth;C1845847:Coarse facial features;C1846459:Slit-like opening of the exterior auditory meatus;C3161330:Intellectual disability, profound;C3553450:Profound global developmental delay;C3714756:Intellectual disability;C4023133:Shortening of all phalanges of fingers;C4024963:Abnormal aggressive, impulsive or violent behavior;C4025741:Clinodactyly of the 5th toe;C4551570:2-3 toe syndactyly Pathogenic:1
-
Center for Personalized Medicine, Children's Hospital Los Angeles
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hirschsprung disease, susceptibility to, 1 Uncertain:1
Apr 01, 2015
Department of Genetics, Reproduction and Fetal Medicine., Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del RocΓ­o/CSIC/University of Seville.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

tegafur response - Toxicity Other:1
May 24, 2021
PharmGKB
Significance: drug response
Review Status: reviewed by expert panel
Collection Method: curation

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
May 24, 2021
PharmGKB
Significance: drug response
Review Status: reviewed by expert panel
Collection Method: curation

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
May 24, 2021
PharmGKB
Significance: drug response
Review Status: reviewed by expert panel
Collection Method: curation

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
May 24, 2021
PharmGKB
Significance: drug response
Review Status: reviewed by expert panel
Collection Method: curation

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

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Uncertain
0.12
CADD
Pathogenic
32
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
5.3

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.95
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.99
Position offset: 1

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: rs3918290; hg19: chr1-97915614; API