NM_000110.4:c.1601G>A

Variant names:

• chr1-97515865-C-T
• rs1801158
• NM_000110.4:c.1601G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000110.4(DPYD):​c.1601G>A​(p.Ser534Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0188 in 1,612,856 control chromosomes in the GnomAD database, including 337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Synonymous variant affecting the same amino acid position (i.e. S534S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (26 hom., cov: 32)
  • Exomes 𝑓: 0.019 (311 hom.)
• Consequence: DPYD NM_000110.4 missense
• Clinical Significance: drug response reviewed by expert panel U:1 B:8 O:3
• Conservation: PhyloP100: 5.71
• Publications: 115 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0098076165).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0137 (2086/152056) while in subpopulation NFE AF = 0.0196 (1330/67912). AF 95% confidence interval is 0.0187. There are 26 homozygotes in GnomAd4. There are 1012 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

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.1601G>A	p.Ser534Asn	missense	Exon 13 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.1601G>A	p.Ser534Asn	missense	Exon 13 of 23	ENSP00000359211.3
	DPYD	ENST00000876340.1		c.1769G>A	p.Ser590Asn	missense	Exon 14 of 24	ENSP00000546399.1
	DPYD	ENST00000969915.1		c.1601G>A	p.Ser534Asn	missense	Exon 13 of 24	ENSP00000639974.1

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2084 AN: 151938 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00396

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0173

GnomAD2 exomes AF: 0.0147 AC: 3683 AN: 250562 AF XY: 0.0147

Gnomad AFR exome AF: 0.00382

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0302

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0135

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0175

GnomAD4 exome AF: 0.0193 AC: 28204 AN: 1460800 Hom.: 311 Cov.: 33 AF XY: 0.0189 AC XY: 13709 AN XY: 726732

African (AFR) AF: 0.00320 AC: 107 AN: 33428

American (AMR) AF: 0.0120 AC: 536 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.0316 AC: 824 AN: 26082

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39684

South Asian (SAS) AF: 0.00867 AC: 748 AN: 86240

European-Finnish (FIN) AF: 0.0139 AC: 742 AN: 53384

Middle Eastern (MID) AF: 0.0330 AC: 190 AN: 5762

European-Non Finnish (NFE) AF: 0.0215 AC: 23872 AN: 1111298

Other (OTH) AF: 0.0196 AC: 1183 AN: 60314

GnomAD4 genome AF: 0.0137 AC: 2086 AN: 152056 Hom.: 26 Cov.: 32 AF XY: 0.0136 AC XY: 1012 AN XY: 74312

African (AFR) AF: 0.00395 AC: 164 AN: 41552

American (AMR) AF: 0.0152 AC: 232 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 115 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5144

South Asian (SAS) AF: 0.00726 AC: 35 AN: 4822

European-Finnish (FIN) AF: 0.0152 AC: 161 AN: 10610

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0196 AC: 1330 AN: 67912

Other (OTH) AF: 0.0171 AC: 36 AN: 2104

Alfa AF: 0.0186 Hom.: 109

Bravo AF: 0.0133

TwinsUK AF: 0.0216 AC: 80

ALSPAC AF: 0.0202 AC: 78

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0202 AC: 174

ExAC AF: 0.0141 AC: 1712

Asia WGS AF: 0.00491 AC: 18 AN: 3478

EpiCase AF: 0.0246

EpiControl AF: 0.0240

ClinVar

ClinVar submissions as Germline

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	3	Dihydropyrimidine dehydrogenase deficiency (4)
-	-	3	not provided (4)
-	-	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	0.27
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0098	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.26
MPC		0.055
ClinPred		0.032	T
GERP RS		5.2
Varity_R		0.48
gMVP		0.77
Mutation Taster		=75/25	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1801158; hg19: chr1-97981421;