1-97305364-C-T

Variant names:

• chr1-97305364-C-T
• rs1801160
• NM_000110.4:c.2194G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V732G) has been classified as Uncertain significance.

• 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
• Publications: 156 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043622553).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0859 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000110.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYD	NM_000110.4	MANE Select	c.2194G>A	p.Val732Ile	missense	Exon 18 of 23	NP_000101.2
	DPYD-AS1	NR_046590.1		n.129-825C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYD	ENST00000370192.8	TSL:1 MANE Select	c.2194G>A	p.Val732Ile	missense	Exon 18 of 23	ENSP00000359211.3
	DPYD-AS1	ENST00000422980.1	TSL:3	n.129-825C>T		intron	N/A

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

GnomAD2 exomes AF: 0.0469 AC: 11760 AN: 250888 AF XY: 0.0513

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 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

African (AFR) AF: 0.0256 AC: 854 AN: 33378

American (AMR) AF: 0.0279 AC: 1244 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2814 AN: 26052

East Asian (EAS) AF: 0.0190 AC: 755 AN: 39652

South Asian (SAS) AF: 0.0964 AC: 8317 AN: 86246

European-Finnish (FIN) AF: 0.0234 AC: 1250 AN: 53394

Middle Eastern (MID) AF: 0.125 AC: 721 AN: 5750

European-Non Finnish (NFE) AF: 0.0450 AC: 49981 AN: 1110880

Other (OTH) AF: 0.0555 AC: 3342 AN: 60268

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

African (AFR) AF: 0.0245 AC: 1017 AN: 41518

American (AMR) AF: 0.0459 AC: 699 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 370 AN: 3464

East Asian (EAS) AF: 0.0154 AC: 79 AN: 5132

South Asian (SAS) AF: 0.0930 AC: 447 AN: 4806

European-Finnish (FIN) AF: 0.0221 AC: 234 AN: 10600

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0452 AC: 3070 AN: 67902

Other (OTH) AF: 0.0602 AC: 127 AN: 2108

Alfa AF: 0.0468 Hom.: 669

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

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26804652, 29769267)

Diasio Lab, Mayo Clinic

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DPYD: BP4, BS1, BS2

not specified Benign:2

Jun 16, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 17, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DPYD-related disorder Benign:1

Mar 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 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

Mar 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

Mar 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 v4.9

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
PhyloP100		7.5
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
Mutation Taster		=74/26	polymorphism (auto)

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

Other links and lift over

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