rs1801265

Variant names:

• chr1-97883329-A-G
• rs1801265
• NM_000110.4:c.85T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-97883329-A-G
• chr1-97883329-A-C
• chr1-97883329-A-T

Variant summary

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

The NM_000110.4(DPYD):​c.85T>C​(p.Cys29Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,612,580 control chromosomes in the GnomAD database, including 44,075 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict 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. C29Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.27 (6329 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37746 hom.)
• Consequence: DPYD NM_000110.4 missense
• Clinical Significance: drug response reviewed by expert panel P:1 B:3 O:2
• Conservation: PhyloP100: 1.65
• Publications: 239 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=0.0027006269).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.399 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.85T>C	p.Cys29Arg	missense	Exon 2 of 23	NP_000101.2	Q12882-1
	DPYD	NM_001160301.1		c.85T>C	p.Cys29Arg	missense	Exon 2 of 6	NP_001153773.1	Q12882-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYD	ENST00000370192.8	TSL:1 MANE Select	c.85T>C	p.Cys29Arg	missense	Exon 2 of 23	ENSP00000359211.3	Q12882-1
	DPYD	ENST00000306031.5	TSL:1	c.85T>C	p.Cys29Arg	missense	Exon 2 of 6	ENSP00000307107.5	Q12882-2
	DPYD	ENST00000876340.1		c.85T>C	p.Cys29Arg	missense	Exon 2 of 24	ENSP00000546399.1

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41507 AN: 151914 Hom.: 6303 Cov.: 32

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0721

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.256

GnomAD4 exome AF: 0.221 AC: 323245 AN: 1460548 Hom.: 37746 Cov.: 32 AF XY: 0.222 AC XY: 161542 AN XY: 726642

African (AFR) AF: 0.413 AC: 13788 AN: 33424

American (AMR) AF: 0.214 AC: 9572 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 3005 AN: 26096

East Asian (EAS) AF: 0.0516 AC: 2045 AN: 39624

South Asian (SAS) AF: 0.253 AC: 21801 AN: 86222

European-Finnish (FIN) AF: 0.288 AC: 15362 AN: 53376

Middle Eastern (MID) AF: 0.234 AC: 1350 AN: 5758

European-Non Finnish (NFE) AF: 0.219 AC: 242879 AN: 1111048

Other (OTH) AF: 0.223 AC: 13443 AN: 60322

GnomAD4 genome AF: 0.274 AC: 41589 AN: 152032 Hom.: 6329 Cov.: 32 AF XY: 0.273 AC XY: 20262 AN XY: 74276

African (AFR) AF: 0.404 AC: 16752 AN: 41462

American (AMR) AF: 0.248 AC: 3779 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 384 AN: 3470

East Asian (EAS) AF: 0.0719 AC: 370 AN: 5144

South Asian (SAS) AF: 0.247 AC: 1191 AN: 4822

European-Finnish (FIN) AF: 0.282 AC: 2987 AN: 10582

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15323 AN: 67972

Other (OTH) AF: 0.254 AC: 537 AN: 2114

Alfa AF: 0.229 Hom.: 20285

Bravo AF: 0.273

ClinVar

ClinVar submissions

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
1	-	-	Dihydropyrimidine dehydrogenase deficiency (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	0.043
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DEOGEN2	Benign	0.059	T
LIST_S2	Benign	0.023	T
MetaRNN	Benign	0.0027	T
PhyloP100		1.6
Sift4G	Benign	0.43	T
Vest4		0.085
gMVP		0.61

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1801265; hg19: chr1-98348885;