Variant 1-97450058-C-T details in Genebe, Genetics Data Aggregator

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 0.053281352 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: {not_provided=2, Pathogenic=15, Likely_pathogenic=1, drug_response=4}. 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/exons	MANE	Protein	UniProt
DPYD	NM_000110.4 linkuse as main transcript	c.1905+1G>A		splice_donor_variant, intron_variant		ENST00000370192.8	NP_000101.2	Q12882-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8 linkuse as main transcript	c.1905+1G>A		splice_donor_variant, intron_variant		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:18Uncertain:1Other:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency

Pathogenic:9Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1999	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	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/. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	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. -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 24, 2016	- -

not provided

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	DPYD: PM3:Strong, PP4:Moderate, PS3:Moderate, PVS1:Moderate, PM2:Supporting -
not provided, no classification provided	literature only	Diasio Lab, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 09, 2019	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 -

Fluorouracil response

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 04, 2016	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2021

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

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

-

- -

Hirschsprung disease, susceptibility to, 1

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Genetics, Reproduction and Fetal Medicine., Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville.

Apr 01, 2015

- -

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

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.

1-97450058-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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