1-97573863-C-T

Position:

chr1-97573863-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_StrongBP7BS1BS2

The NM_000110.4(DPYD):c.1236G>A(p.Glu412Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,613,680 control chromosomes in the GnomAD database, including 358 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.013 ( 23 hom., cov: 32)

Exomes 𝑓: 0.019 ( 335 hom. )

Consequence

DPYD
NM_000110.4 synonymous

Scores

Clinical Significance

drug response reviewed by expert panel B:5O:3

Conservation

PhyloP100: 0.403

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]

DPYD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant 1-97573863-C-T is Benign according to our data. Variant chr1-97573863-C-T is described in ClinVar as [drug_response]. Clinvar id is 100100.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, not_provided=1, Benign=4, drug_response=2}. Variant chr1-97573863-C-T is described in Lovd as [Pathogenic]. Variant chr1-97573863-C-T is described in Lovd as [Benign]. Variant chr1-97573863-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.403 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0131 (1993/152190) while in subpopulation NFE AF= 0.0214 (1455/68002). AF 95% confidence interval is 0.0205. There are 23 homozygotes in gnomad4. There are 935 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYD	NM_000110.4 linkuse as main transcript	c.1236G>A	p.Glu412Glu	synonymous_variant	11/23	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.1236G>A	p.Glu412Glu	synonymous_variant	11/23	1	NM_000110.4	ENSP00000359211.3		Q12882-1

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1994

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00297

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.00728

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0161

Gnomad FIN

AF:

0.0142

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0214

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.0141

AC:

3543

AN:

251150

Hom.:

AF XY:

0.0151

AC XY:

2048

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.00449

Gnomad ASJ exome

AF:

0.00665

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0173

Gnomad FIN exome

AF:

0.0122

Gnomad NFE exome

AF:

0.0211

Gnomad OTH exome

AF:

0.0142

GnomAD4 exome

AF:

0.0194

AC:

28307

AN:

1461490

Hom.:

335

Cov.:

AF XY:

0.0194

AC XY:

14130

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.00278

Gnomad4 AMR exome

AF:

0.00483

Gnomad4 ASJ exome

AF:

0.00586

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0173

Gnomad4 FIN exome

AF:

0.0133

Gnomad4 NFE exome

AF:

0.0221

Gnomad4 OTH exome

AF:

0.0161

GnomAD4 genome

AF:

0.0131

AC:

1993

AN:

152190

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

935

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.00294

Gnomad4 AMR

AF:

0.00727

Gnomad4 ASJ

AF:

0.00547

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.0161

Gnomad4 FIN

AF:

0.0142

Gnomad4 NFE

AF:

0.0214

Gnomad4 OTH

AF:

0.00993

Alfa

AF:

0.0180

Hom.:

Bravo

AF:

0.0120

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.0183

EpiControl

AF:

0.0191

ClinVar

Significance: drug response

Submissions summary: Benign:5Other:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

not provided, no classification provided	literature only	Diasio Lab, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	DPYD: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 21, 2017	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 19, 2018	Variant summary: DPYD c.1236G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.014 in 276814 control chromosomes in the gnomAD database, including 39 homozygotes. The observed variant frequency is approximately 5.66 fold of the estimated maximal expected allele frequency for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency phenotype (0.0025), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1236G>A in individuals affected with Dihydropyrimidine Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. One other clinical diagnostic laboratory classified this variant as benign via ClinVar. Based on the evidence outlined above, the variant was classified as benign. -

Dihydropyrimidine dehydrogenase deficiency

Benign:1

Likely benign, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

fluorouracil response - Toxicity

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Oct 27, 2022

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

capecitabine response - Toxicity

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Oct 26, 2022

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

6.8

DANN

Benign

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over