NM_000110.4:c.1896T>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_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
• Publications: 75 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 Gene-Disease associations (from GenCC):

• dihydropyrimidine dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• 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.

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.1896T>C	p.Phe632Phe	synonymous	Exon 14 of 23	NP_000101.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYD	ENST00000370192.8	TSL:1 MANE Select	c.1896T>C	p.Phe632Phe	synonymous	Exon 14 of 23	ENSP00000359211.3
	DPYD	ENST00000876340.1		c.2064T>C	p.Phe688Phe	synonymous	Exon 15 of 24	ENSP00000546399.1
	DPYD	ENST00000969915.1		c.1896T>C	p.Phe632Phe	synonymous	Exon 14 of 24	ENSP00000639974.1

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

African (AFR) AF: 0.0183 AC: 612 AN: 33470

American (AMR) AF: 0.0853 AC: 3812 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00991 AC: 259 AN: 26126

East Asian (EAS) AF: 0.131 AC: 5185 AN: 39680

South Asian (SAS) AF: 0.0346 AC: 2985 AN: 86254

European-Finnish (FIN) AF: 0.0450 AC: 2402 AN: 53416

Middle Eastern (MID) AF: 0.0149 AC: 86 AN: 5764

European-Non Finnish (NFE) AF: 0.0453 AC: 50339 AN: 1111792

Other (OTH) 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

African (AFR) AF: 0.0215 AC: 893 AN: 41542

American (AMR) AF: 0.0727 AC: 1111 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.124 AC: 640 AN: 5180

South Asian (SAS) AF: 0.0387 AC: 187 AN: 4826

European-Finnish (FIN) AF: 0.0483 AC: 513 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0452 AC: 3075 AN: 68010

Other (OTH) AF: 0.0393 AC: 83 AN: 2112

Alfa AF: 0.0434 Hom.: 731

Bravo AF: 0.0446

Asia WGS AF: 0.0850 AC: 296 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Dihydropyrimidine dehydrogenase deficiency (1)
-	-	1	not specified (1)
-	-	-	capecitabine response - Toxicity (1)
-	-	-	fluorouracil response - Toxicity (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.1
DANN	Benign	0.61
PhyloP100		0.29
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

Other links and lift over

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