1-97699535-T-C

Variant names:

• chr1-97699535-T-C
• rs2297595
• NM_000110.4:c.496A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000110.4(DPYD):​c.496A>G​(p.Met166Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0895 in 1,612,978 control chromosomes in the GnomAD database, including 7,345 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. M166T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.080 (626 hom., cov: 32)
  • Exomes 𝑓: 0.090 (6719 hom.)
• Consequence: DPYD NM_000110.4 missense
• Clinical Significance: drug response reviewed by expert panel U:1 B:5 O:3
• Conservation: PhyloP100: 7.56
• Publications: 168 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019071698).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0991 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYD	NM_000110.4	MANE Select	c.496A>G	p.Met166Val	missense	Exon 6 of 23	NP_000101.2	Q12882-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYD	ENST00000370192.8	TSL:1 MANE Select	c.496A>G	p.Met166Val	missense	Exon 6 of 23	ENSP00000359211.3	Q12882-1
	DPYD	ENST00000876340.1		c.496A>G	p.Met166Val	missense	Exon 6 of 24	ENSP00000546399.1
	DPYD	ENST00000969915.1		c.496A>G	p.Met166Val	missense	Exon 6 of 24	ENSP00000639974.1

Frequencies

GnomAD3 genomes AF: 0.0801 AC: 12181 AN: 152000 Hom.: 626 Cov.: 32

Gnomad AFR AF: 0.0336

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.0666

Gnomad ASJ AF: 0.0842

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.0734

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0817

GnomAD2 exomes AF: 0.0853 AC: 21419 AN: 251038 AF XY: 0.0899

Gnomad AFR exome AF: 0.0334

Gnomad AMR exome AF: 0.0359

Gnomad ASJ exome AF: 0.0775

Gnomad EAS exome AF: 0.0158

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.0883

GnomAD4 exome AF: 0.0905 AC: 132173 AN: 1460860 Hom.: 6719 Cov.: 31 AF XY: 0.0920 AC XY: 66851 AN XY: 726740

African (AFR) AF: 0.0326 AC: 1089 AN: 33442

American (AMR) AF: 0.0388 AC: 1733 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0767 AC: 2002 AN: 26112

East Asian (EAS) AF: 0.0179 AC: 710 AN: 39678

South Asian (SAS) AF: 0.0900 AC: 7762 AN: 86228

European-Finnish (FIN) AF: 0.171 AC: 9141 AN: 53408

Middle Eastern (MID) AF: 0.146 AC: 842 AN: 5758

European-Non Finnish (NFE) AF: 0.0934 AC: 103747 AN: 1111164

Other (OTH) AF: 0.0853 AC: 5147 AN: 60352

GnomAD4 genome AF: 0.0802 AC: 12194 AN: 152118 Hom.: 626 Cov.: 32 AF XY: 0.0833 AC XY: 6196 AN XY: 74342

African (AFR) AF: 0.0339 AC: 1409 AN: 41540

American (AMR) AF: 0.0665 AC: 1014 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0842 AC: 292 AN: 3468

East Asian (EAS) AF: 0.0162 AC: 84 AN: 5182

South Asian (SAS) AF: 0.0732 AC: 353 AN: 4822

European-Finnish (FIN) AF: 0.176 AC: 1856 AN: 10566

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6871 AN: 67970

Other (OTH) AF: 0.0814 AC: 172 AN: 2114

Alfa AF: 0.0892 Hom.: 3346

Bravo AF: 0.0690

TwinsUK AF: 0.0879 AC: 326

ALSPAC AF: 0.0872 AC: 336

ESP6500AA AF: 0.0409 AC: 180

ESP6500EA AF: 0.0991 AC: 852

ExAC AF: 0.0863 AC: 10475

Asia WGS AF: 0.0480 AC: 169 AN: 3478

EpiCase AF: 0.101

EpiControl AF: 0.0995

ClinVar

ClinVar submissions

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	Dihydropyrimidine dehydrogenase deficiency (2)
-	-	2	not provided (3)
-	-	1	DPYD-related disorder (1)
-	-	1	not specified (1)
-	-	-	capecitabine response - Toxicity (1)
-	-	-	fluorouracil response - Toxicity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0019	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.28
MPC		0.36
ClinPred		0.0057	T
GERP RS		5.3
Varity_R		0.76
gMVP		0.79
Mutation Taster		=82/18	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: rs2297595; hg19: chr1-98165091; COSMIC: COSV64612232;