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

Variant names:

• chr1-97450058-C-T
• rs3918290
• NM_000110.4:c.1905+1G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PVS1_Moderate PP5_Strong BS1_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 (★★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (38 hom.)
• Consequence: DPYD NM_000110.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: drug response reviewed by expert panel P:19 U:1 B:1 O:6
• Conservation: PhyloP100: 7.57

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]

ACMG classification

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: {Likely_pathogenic=1, drug_response=4, Benign=1, Pathogenic=16, 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
DPYD	NM_000110.4	c.1905+1G>A		splice_donor_variant, intron_variant	Intron 14 of 22	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8	c.1905+1G>A		splice_donor_variant, intron_variant	Intron 14 of 22	1	NM_000110.4	ENSP00000359211.3

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 693 AN: 152154 Hom.: 3 Cov.: 32

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

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

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

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:19 Uncertain:1 Benign:1 Other:6

Revision: reviewed by expert panel

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency Pathogenic:9 Other:1

-

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/. -

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. -

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 01, 2021

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2022

3billion

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. -

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

- -

Mar 24, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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:6 Benign:1 Other:1

-

Diasio Lab, Mayo Clinic

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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) -

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 -

Nov 19, 2018

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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 -

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

- -

Fluorouracil response Pathogenic:2

May 04, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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. -

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 Rocío/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

Other links and lift over

dbSNP: rs3918290; hg19: chr1-97915614;