1-97579893-G-C

Variant names:

• chr1-97579893-G-C
• rs75017182
• NM_000110.4:c.1129-5923C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BS1_Supporting BS2

The NM_000110.4(DPYD):​c.1129-5923C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 152,204 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency: Genomes: 𝑓 0.013 (23 hom., cov: 33)
• Consequence: DPYD NM_000110.4 intron
• Clinical Significance: drug response reviewed by expert panel B:2 O:3
• Conservation: PhyloP100: 0.0950
• Publications: 102 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 -4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0131 (1993/152204) while in subpopulation NFE AF = 0.0214 (1454/67990). AF 95% confidence interval is 0.0205. There are 23 homozygotes in GnomAd4. There are 936 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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 23 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.1129-5923C>G		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.1129-5923C>G		intron	N/A	ENSP00000359211.3
	DPYD	ENST00000876340.1		c.1297-5923C>G		intron	N/A	ENSP00000546399.1
	DPYD	ENST00000969915.1		c.1129-5923C>G		intron	N/A	ENSP00000639974.1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1994 AN: 152086 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00747

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0100

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0131 AC: 1993 AN: 152204 Hom.: 23 Cov.: 33 AF XY: 0.0126 AC XY: 936 AN XY: 74402

African (AFR) AF: 0.00291 AC: 121 AN: 41554

American (AMR) AF: 0.00746 AC: 114 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0162 AC: 78 AN: 4812

European-Finnish (FIN) AF: 0.0142 AC: 150 AN: 10586

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0214 AC: 1454 AN: 67990

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00476 Hom.: 1

Bravo AF: 0.0120

Asia WGS AF: 0.00867 AC: 30 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	DPYD-related disorder (1)
-	-	1	not provided (1)
-	-	-	capecitabine response - Toxicity (1)
-	-	-	fluorouracil response - Other (1)
-	-	-	fluorouracil response - Toxicity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Pathogenic	35
DANN	Benign	0.68
PhyloP100		0.095
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.68		Position offset: 44
DS_DG_spliceai		0.77		Position offset: 1

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

Other links and lift over

dbSNP: rs75017182; hg19: chr1-98045449;