rs17376848

Variant names:

• chr1-97450068-A-G
• rs17376848
• NM_000110.4:c.1896T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Strong BP7 BA1

The NM_000110.4(DPYD):​c.1896T>C​(p.Phe632Phe) 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

Our verdict: Benign. The variant received -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, not_provided=1, Benign=2}. 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 rank	MANE	Protein	UniProt
DPYD	NM_000110.4	c.1896T>C	p.Phe632Phe	synonymous_variant	Exon 14 of 23	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8	c.1896T>C	p.Phe632Phe	synonymous_variant	Exon 14 of 23	1	NM_000110.4	ENSP00000359211.3

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

GnomAD2 exomes AF: 0.0510 AC: 12816 AN: 251280 AF XY: 0.0490

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 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 AC: 612 AN: 33470

Gnomad4 AMR exome AF: 0.0853 AC: 3812 AN: 44692

Gnomad4 ASJ exome AF: 0.00991 AC: 259 AN: 26126

Gnomad4 EAS exome AF: 0.131 AC: 5185 AN: 39680

Gnomad4 SAS exome AF: 0.0346 AC: 2985 AN: 86254

Gnomad4 FIN exome AF: 0.0450 AC: 2402 AN: 53416

Gnomad4 NFE exome AF: 0.0453 AC: 50339 AN: 1111792

Gnomad4 Remaining exome AF: 0.0468 AC: 2823 AN: 60382

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 AC: 0.0214963 AN: 0.0214963

Gnomad4 AMR AF: 0.0727 AC: 0.0727189 AN: 0.0727189

Gnomad4 ASJ AF: 0.0130 AC: 0.0129608 AN: 0.0129608

Gnomad4 EAS AF: 0.124 AC: 0.123552 AN: 0.123552

Gnomad4 SAS AF: 0.0387 AC: 0.0387484 AN: 0.0387484

Gnomad4 FIN AF: 0.0483 AC: 0.0482869 AN: 0.0482869

Gnomad4 NFE AF: 0.0452 AC: 0.0452139 AN: 0.0452139

Gnomad4 OTH AF: 0.0393 AC: 0.0392992 AN: 0.0392992

Alfa AF: 0.0434 Hom.: 731

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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dihydropyrimidine dehydrogenase deficiency Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: 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 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

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

not provided Other:1

-

Diasio Lab, Mayo Clinic

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.1
DANN	Benign	0.61
Mutation Taster		=99/1	polymorphism (auto)

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;