rs45589337

Variant names:

• chr1-97679170-T-C
• rs45589337
• NM_000110.4:c.775A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000110.4(DPYD):​c.775A>G​(p.Lys259Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00665 in 1,564,148 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (39 hom.)
• Consequence: DPYD NM_000110.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.87
• Publications: 35 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 (MetaRNN=0.014378965).
• BP6: Variant 1-97679170-T-C is Benign according to our data. Variant chr1-97679170-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235464.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00514 (783/152264) while in subpopulation NFE AF = 0.00748 (509/68008). AF 95% confidence interval is 0.00695. There are 6 homozygotes in GnomAd4. There are 351 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYD	NM_000110.4	MANE Select	c.775A>G	p.Lys259Glu	missense	Exon 8 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.775A>G	p.Lys259Glu	missense	Exon 8 of 23	ENSP00000359211.3	Q12882-1
	DPYD	ENST00000876340.1		c.943A>G	p.Lys315Glu	missense	Exon 9 of 24	ENSP00000546399.1
	DPYD	ENST00000969915.1		c.775A>G	p.Lys259Glu	missense	Exon 8 of 24	ENSP00000639974.1

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 782 AN: 152146 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00594

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00748

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00620 AC: 1365 AN: 220112 AF XY: 0.00636

Gnomad AFR exome AF: 0.00146

Gnomad AMR exome AF: 0.00316

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00712

Gnomad NFE exome AF: 0.00822

Gnomad OTH exome AF: 0.00852

GnomAD4 exome AF: 0.00681 AC: 9620 AN: 1411884 Hom.: 39 Cov.: 24 AF XY: 0.00679 AC XY: 4766 AN XY: 701658

African (AFR) AF: 0.000739 AC: 24 AN: 32456

American (AMR) AF: 0.00342 AC: 147 AN: 42936

Ashkenazi Jewish (ASJ) AF: 0.0162 AC: 407 AN: 25126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39100

South Asian (SAS) AF: 0.00521 AC: 418 AN: 80262

European-Finnish (FIN) AF: 0.00891 AC: 458 AN: 51400

Middle Eastern (MID) AF: 0.00679 AC: 33 AN: 4862

European-Non Finnish (NFE) AF: 0.00719 AC: 7746 AN: 1077446

Other (OTH) AF: 0.00664 AC: 387 AN: 58296

GnomAD4 genome AF: 0.00514 AC: 783 AN: 152264 Hom.: 6 Cov.: 32 AF XY: 0.00471 AC XY: 351 AN XY: 74464

African (AFR) AF: 0.00137 AC: 57 AN: 41568

American (AMR) AF: 0.00360 AC: 55 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 63 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4826

European-Finnish (FIN) AF: 0.00594 AC: 63 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00748 AC: 509 AN: 68008

Other (OTH) AF: 0.00522 AC: 11 AN: 2108

Alfa AF: 0.00644 Hom.: 24

Bravo AF: 0.00511

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00747 AC: 64

ExAC AF: 0.00611 AC: 736

Asia WGS AF: 0.00145 AC: 5 AN: 3464

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	1	1	Dihydropyrimidine dehydrogenase deficiency (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.098
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.9
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.34	B
Vest4		0.85
MVP		0.92
MPC		0.093
ClinPred		0.025	T
GERP RS		4.5
Varity_R		0.37
gMVP		0.81
Mutation Taster		=83/17	polymorphism

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: rs45589337; hg19: chr1-98144726; COSMIC: COSV99058634;