rs56293913

Variant names:

• chr1-97573985-A-G
• rs56293913
• NM_000110.4:c.1129-15T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000110.4(DPYD):​c.1129-15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,612,456 control chromosomes in the GnomAD database, including 9,385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (849 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8536 hom.)
• Consequence: DPYD NM_000110.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 1.39
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-97573985-A-G is Benign according to our data. Variant chr1-97573985-A-G is described in ClinVar as Benign. ClinVar VariationId is 100103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.114 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.1129-15T>C		intron	N/A	NP_000101.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYD	ENST00000370192.8	TSL:1 MANE Select	c.1129-15T>C		intron	N/A	ENSP00000359211.3
	DPYD	ENST00000876340.1		c.1297-15T>C		intron	N/A	ENSP00000546399.1
	DPYD	ENST00000969915.1		c.1129-15T>C		intron	N/A	ENSP00000639974.1

Frequencies

GnomAD3 genomes AF: 0.0957 AC: 14560 AN: 152086 Hom.: 849 Cov.: 32

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.0717

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.0621

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.0989

GnomAD2 exomes AF: 0.0956 AC: 23775 AN: 248638 AF XY: 0.0987

Gnomad AFR exome AF: 0.0582

Gnomad AMR exome AF: 0.0413

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.0155

Gnomad FIN exome AF: 0.189

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.103 AC: 150070 AN: 1460252 Hom.: 8536 Cov.: 32 AF XY: 0.103 AC XY: 75163 AN XY: 726364

African (AFR) AF: 0.0581 AC: 1943 AN: 33414

American (AMR) AF: 0.0447 AC: 1990 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2867 AN: 26106

East Asian (EAS) AF: 0.0174 AC: 689 AN: 39612

South Asian (SAS) AF: 0.0769 AC: 6626 AN: 86154

European-Finnish (FIN) AF: 0.184 AC: 9807 AN: 53326

Middle Eastern (MID) AF: 0.168 AC: 970 AN: 5760

European-Non Finnish (NFE) AF: 0.107 AC: 119181 AN: 1111008

Other (OTH) AF: 0.0994 AC: 5997 AN: 60308

GnomAD4 genome AF: 0.0957 AC: 14566 AN: 152204 Hom.: 849 Cov.: 32 AF XY: 0.0971 AC XY: 7226 AN XY: 74408

African (AFR) AF: 0.0590 AC: 2452 AN: 41564

American (AMR) AF: 0.0716 AC: 1094 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 402 AN: 3464

East Asian (EAS) AF: 0.0158 AC: 82 AN: 5184

South Asian (SAS) AF: 0.0618 AC: 298 AN: 4824

European-Finnish (FIN) AF: 0.185 AC: 1955 AN: 10584

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7894 AN: 67980

Other (OTH) AF: 0.0988 AC: 209 AN: 2116

Alfa AF: 0.104 Hom.: 1492

Bravo AF: 0.0853

Asia WGS AF: 0.0430 AC: 149 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Dihydropyrimidine dehydrogenase deficiency (2)
-	-	1	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.9
DANN	Benign	0.81
PhyloP100		1.4
Mutation Taster		=100/0	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: rs56293913; hg19: chr1-98039541; COSMIC: COSV64593293;