rs67376798

Variant names:

• chr1-97082391-T-A
• rs67376798
• NM_000110.4:c.2846A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 5P and 10B. PS3 PP3 BP4_Moderate BS1 BS2

The NM_000110.4(DPYD):​c.2846A>T​(p.Asp949Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00504 in 1,613,660 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). ClinVar reports functional evidence for this variant: "SCV000695412: Experimental evidence evaluating an impact on protein function demonstrated the variant to result in decreased enzyme activity (e.g. van Kuilenburg_2002, Offer_2014, van Kuilenburg_2016, Henricks_2017). PMID:29152729, 23988873, 30510603, 33232506, 26265346, 31745289, 30114658, 24648345, 32595208, 16115930, 26804652, 11988088, 11156223." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (29 hom.)
• Consequence: DPYD NM_000110.4 missense
• Clinical Significance: drug response reviewed by expert panel P:8 U:1 B:2 O:6
• Conservation: PhyloP100: 7.82
• Publications: 404 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: Likely_benign. The variant received -5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000695412: Experimental evidence evaluating an impact on protein function demonstrated the variant to result in decreased enzyme activity (e.g. van Kuilenburg_2002, Offer_2014, van Kuilenburg_2016, Henricks_2017). PMID: 29152729, 23988873, 30510603, 33232506, 26265346, 31745289, 30114658, 24648345, 32595208, 16115930, 26804652, 11988088, 11156223.; SCV002766693: Functional studies show that this variant reduces enzyme activity (PMIDs: 26804652, 24648345); SCV004812380: DPD enzyme activity assays in cell lines showed partially reduced activity indicating that this variant impacts protein function (PMID: 24648345, 26804652).
• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Eigen, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.13372508).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00328 (499/152236) while in subpopulation NFE AF = 0.00605 (411/67978). AF 95% confidence interval is 0.00556. There are 3 homozygotes in GnomAd4. There are 211 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.2846A>T	p.Asp949Val	missense	Exon 22 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.2846A>T	p.Asp949Val	missense	Exon 22 of 23	ENSP00000359211.3	Q12882-1
	DPYD	ENST00000876340.1		c.3014A>T	p.Asp1005Val	missense	Exon 23 of 24	ENSP00000546399.1
	DPYD	ENST00000969915.1		c.2951A>T	p.Asp984Val	missense	Exon 23 of 24	ENSP00000639974.1

Frequencies

GnomAD3 genomes AF: 0.00328 AC: 499 AN: 152118 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00605

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00285 AC: 715 AN: 251256 AF XY: 0.00286

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00508

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00523 AC: 7640 AN: 1461424 Hom.: 29 Cov.: 33 AF XY: 0.00509 AC XY: 3703 AN XY: 727012

African (AFR) AF: 0.00105 AC: 35 AN: 33468

American (AMR) AF: 0.00235 AC: 105 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39666

South Asian (SAS) AF: 0.000522 AC: 45 AN: 86248

European-Finnish (FIN) AF: 0.000487 AC: 26 AN: 53396

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.00645 AC: 7172 AN: 1111666

Other (OTH) AF: 0.00409 AC: 247 AN: 60378

GnomAD4 genome AF: 0.00328 AC: 499 AN: 152236 Hom.: 3 Cov.: 32 AF XY: 0.00283 AC XY: 211 AN XY: 74456

African (AFR) AF: 0.00118 AC: 49 AN: 41566

American (AMR) AF: 0.00170 AC: 26 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00605 AC: 411 AN: 67978

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00517 Hom.: 1

Bravo AF: 0.00345

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00263 AC: 319

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00524

EpiControl AF: 0.00492

ClinVar

ClinVar submissions

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Dihydropyrimidine dehydrogenase deficiency (6)
1	-	2	not provided (4)
1	-	-	DPYD-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	-	-	capecitabine response - Toxicity (1)
-	-	-	Fluorouracil response (1)
-	-	-	fluorouracil response - Other (1)
-	-	-	fluorouracil response - Toxicity (1)
-	-	-	tegafur response - Toxicity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.13	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.94
MPC		0.22
ClinPred		0.054	T
GERP RS		5.8
Varity_R		0.75
gMVP		0.94
Mutation Taster		=15/85	disease causing

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: rs67376798; hg19: chr1-97547947; COSMIC: COSV100929857;