rs17376848

Positions:

• chr1-97450068-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Strong BP7 BA1

The NM_000110.4(DPYD):​c.1896T>C​(p.Phe632=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0466 in 1,613,826 control chromosomes in the GnomAD database, including 2,196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.044 (194 hom., cov: 32)
  • Exomes 𝑓: 0.047 (2002 hom.)
• Consequence: DPYD NM_000110.4 synonymous
• Clinical Significance: drug response reviewed by expert panel B:2 O:3
• Conservation: PhyloP100: 0.288

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 1-97450068-A-G is Benign according to our data. Variant chr1-97450068-A-G is described in ClinVar as [drug_response]. Clinvar id is 100088.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {drug_response=2, Benign=2, not_provided=1}. Variant chr1-97450068-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.288 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPYD	NM_000110.4	c.1896T>C	p.Phe632=	synonymous_variant	14/23	ENST00000370192.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPYD	ENST00000370192.8	c.1896T>C	p.Phe632=	synonymous_variant	14/23	1	NM_000110.4	P1

Frequencies

GnomAD3 genomes AF: 0.0438 AC: 6666 AN: 152132 Hom.: 195 Cov.: 32

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.0729

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.0391

Gnomad FIN AF: 0.0483

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0388

GnomAD3 exomes AF: 0.0510 AC: 12816 AN: 251280 Hom.: 454 AF XY: 0.0490 AC XY: 6653 AN XY: 135808

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.0873

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.126

Gnomad SAS exome AF: 0.0347

Gnomad FIN exome AF: 0.0480

Gnomad NFE exome AF: 0.0411

Gnomad OTH exome AF: 0.0421

GnomAD4 exome AF: 0.0469 AC: 68503 AN: 1461576 Hom.: 2002 Cov.: 31 AF XY: 0.0458 AC XY: 33324 AN XY: 727076

Gnomad4 AFR exome AF: 0.0183

Gnomad4 AMR exome AF: 0.0853

Gnomad4 ASJ exome AF: 0.00991

Gnomad4 EAS exome AF: 0.131

Gnomad4 SAS exome AF: 0.0346

Gnomad4 FIN exome AF: 0.0450

Gnomad4 NFE exome AF: 0.0453

Gnomad4 OTH exome AF: 0.0468

GnomAD4 genome AF: 0.0438 AC: 6664 AN: 152250 Hom.: 194 Cov.: 32 AF XY: 0.0452 AC XY: 3366 AN XY: 74444

Gnomad4 AFR AF: 0.0215

Gnomad4 AMR AF: 0.0727

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.124

Gnomad4 SAS AF: 0.0387

Gnomad4 FIN AF: 0.0483

Gnomad4 NFE AF: 0.0452

Gnomad4 OTH AF: 0.0393

Alfa AF: 0.0417 Hom.: 321

Bravo AF: 0.0446

Asia WGS AF: 0.0850 AC: 296 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Benign:2 Other:3

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Dihydropyrimidine dehydrogenase deficiency Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of 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

not provided Other:1

not provided, no classification provided

literature only

Diasio Lab, Mayo Clinic

-

- -

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
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.1
DANN	Benign	0.61

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

Other links and lift over

dbSNP: rs17376848; hg19: chr1-97915624; COSMIC: COSV100928729;