1-97305364-C-T

Position:

• chr1-97305364-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Strong BA1

The NM_000110.4(DPYD):​c.2194G>A​(p.Val732Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0467 in 1,612,218 control chromosomes in the GnomAD database, including 2,145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.040 (158 hom., cov: 32)
  • Exomes 𝑓: 0.047 (1987 hom.)
• Consequence: DPYD NM_000110.4 missense
• Clinical Significance: drug response reviewed by expert panel B:6 O:4
• Conservation: PhyloP100: 7.50

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-AS1 (HGNC:40195): (DPYD antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043622553).
• BP6: Variant 1-97305364-C-T is Benign according to our data. Variant chr1-97305364-C-T is described in ClinVar as [drug_response]. Clinvar id is 100080.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=4, not_provided=1, drug_response=3}. Variant chr1-97305364-C-T is described in Lovd as [Benign]. Variant chr1-97305364-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYD	NM_000110.4	c.2194G>A	p.Val732Ile	missense_variant	18/23	ENST00000370192.8	NP_000101.2
DPYD-AS1	NR_046590.1	n.129-825C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8	c.2194G>A	p.Val732Ile	missense_variant	18/23	1	NM_000110.4	ENSP00000359211	P1
DPYD-AS1	ENST00000422980.1	n.129-825C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0401 AC: 6089 AN: 151842 Hom.: 158 Cov.: 32

Gnomad AFR AF: 0.0245

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0460

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.0917

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0604

GnomAD3 exomes AF: 0.0469 AC: 11760 AN: 250888 Hom.: 387 AF XY: 0.0513 AC XY: 6951 AN XY: 135568

Gnomad AFR exome AF: 0.0243

Gnomad AMR exome AF: 0.0259

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.0194

Gnomad SAS exome AF: 0.0975

Gnomad FIN exome AF: 0.0207

Gnomad NFE exome AF: 0.0462

Gnomad OTH exome AF: 0.0606

GnomAD4 exome AF: 0.0474 AC: 69278 AN: 1460258 Hom.: 1987 Cov.: 32 AF XY: 0.0494 AC XY: 35900 AN XY: 726484

Gnomad4 AFR exome AF: 0.0256

Gnomad4 AMR exome AF: 0.0279

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.0190

Gnomad4 SAS exome AF: 0.0964

Gnomad4 FIN exome AF: 0.0234

Gnomad4 NFE exome AF: 0.0450

Gnomad4 OTH exome AF: 0.0555

GnomAD4 genome AF: 0.0401 AC: 6090 AN: 151960 Hom.: 158 Cov.: 32 AF XY: 0.0393 AC XY: 2917 AN XY: 74256

Gnomad4 AFR AF: 0.0245

Gnomad4 AMR AF: 0.0459

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.0154

Gnomad4 SAS AF: 0.0930

Gnomad4 FIN AF: 0.0221

Gnomad4 NFE AF: 0.0452

Gnomad4 OTH AF: 0.0602

Alfa AF: 0.0501 Hom.: 355

Bravo AF: 0.0407

TwinsUK AF: 0.0369 AC: 137

ALSPAC AF: 0.0423 AC: 163

ESP6500AA AF: 0.0309 AC: 136

ESP6500EA AF: 0.0467 AC: 402

ExAC AF: 0.0464 AC: 5633

Asia WGS AF: 0.0450 AC: 155 AN: 3478

EpiCase AF: 0.0534

EpiControl AF: 0.0550

ClinVar

Significance: drug response

Submissions summary: Benign:6 Other:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	DPYD: BP4, BS1, BS2 -
not provided, no classification provided	literature only	Diasio Lab, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 26804652, 29769267) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 16, 2017	- -

DPYD-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Dihydropyrimidine dehydrogenase deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

fluorouracil response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 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

Mar 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

Mar 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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0044	T
MetaSVM	Uncertain	-0.076	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.98	N
REVEL	Uncertain	0.30
Sift	Benign	0.057	T
Sift4G	Uncertain	0.055	T
Polyphen		1.0	D
Vest4		0.18
MPC		0.098
ClinPred		0.013	T
GERP RS		5.5
Varity_R		0.44
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs1801160; hg19: chr1-97770920; COSMIC: COSV64595677;