rs1801159

Variant names:

• chr1-97515839-T-C
• rs1801159
• NM_000110.4:c.1627A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-97515839-T-C
• chr1-97515839-T-A
• chr1-97515839-T-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.1627A>G​(p.Ile543Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,612,714 control chromosomes in the GnomAD database, including 31,976 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2802 hom., cov: 32)
  • Exomes 𝑓: 0.20 (29174 hom.)
• Consequence: DPYD NM_000110.4 missense
• Clinical Significance: drug response reviewed by expert panel B:8 O:3
• Conservation: PhyloP100: 1.40
• Publications: 176 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=0.00896588).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.243 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.1627A>G	p.Ile543Val	missense	Exon 13 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.1627A>G	p.Ile543Val	missense	Exon 13 of 23	ENSP00000359211.3	Q12882-1
	DPYD	ENST00000876340.1		c.1795A>G	p.Ile599Val	missense	Exon 14 of 24	ENSP00000546399.1
	DPYD	ENST00000969915.1		c.1627A>G	p.Ile543Val	missense	Exon 13 of 24	ENSP00000639974.1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28219 AN: 151788 Hom.: 2791 Cov.: 32

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.0961

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.198 AC: 49519 AN: 250532 AF XY: 0.189

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.297

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.254

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.196 AC: 285727 AN: 1460808 Hom.: 29174 Cov.: 34 AF XY: 0.192 AC XY: 139533 AN XY: 726730

African (AFR) AF: 0.154 AC: 5160 AN: 33432

American (AMR) AF: 0.294 AC: 13109 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 5084 AN: 26088

East Asian (EAS) AF: 0.271 AC: 10765 AN: 39684

South Asian (SAS) AF: 0.0957 AC: 8249 AN: 86240

European-Finnish (FIN) AF: 0.168 AC: 8951 AN: 53374

Middle Eastern (MID) AF: 0.150 AC: 865 AN: 5762

European-Non Finnish (NFE) AF: 0.200 AC: 221968 AN: 1111316

Other (OTH) AF: 0.192 AC: 11576 AN: 60312

GnomAD4 genome AF: 0.186 AC: 28273 AN: 151906 Hom.: 2802 Cov.: 32 AF XY: 0.183 AC XY: 13615 AN XY: 74244

African (AFR) AF: 0.159 AC: 6583 AN: 41482

American (AMR) AF: 0.237 AC: 3610 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 673 AN: 3464

East Asian (EAS) AF: 0.255 AC: 1308 AN: 5132

South Asian (SAS) AF: 0.0964 AC: 465 AN: 4826

European-Finnish (FIN) AF: 0.167 AC: 1770 AN: 10598

Middle Eastern (MID) AF: 0.147 AC: 43 AN: 292

European-Non Finnish (NFE) AF: 0.196 AC: 13301 AN: 67882

Other (OTH) AF: 0.189 AC: 399 AN: 2106

Alfa AF: 0.197 Hom.: 13873

Bravo AF: 0.195

TwinsUK AF: 0.202 AC: 750

ALSPAC AF: 0.204 AC: 786

ESP6500AA AF: 0.155 AC: 684

ESP6500EA AF: 0.198 AC: 1704

ExAC AF: 0.192 AC: 23357

Asia WGS AF: 0.192 AC: 669 AN: 3478

EpiCase AF: 0.198

EpiControl AF: 0.200

ClinVar

ClinVar submissions

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	Dihydropyrimidine dehydrogenase deficiency (4)
-	-	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	0.062
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	9.5
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.92
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N
PhyloP100		1.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.73	N
REVEL	Benign	0.12
Sift	Benign	0.11	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.036
MPC		0.048
ClinPred		0.0048	T
GERP RS		-3.1
Varity_R		0.029
gMVP		0.43
Mutation Taster		=98/2	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: rs1801159; hg19: chr1-97981395; COSMIC: COSV64593269;