chr1-97691806-G-A

Variant names:

• chr1-97691806-G-A
• rs74774246
• NM_000110.4:c.681-8C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000110.4(DPYD):​c.681-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,612,308 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (44 hom.)
• Consequence: DPYD NM_000110.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002168
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0560
• Publications: 4 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=-0.89).
• BP6: Variant 1-97691806-G-A is Benign according to our data. Variant chr1-97691806-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 585804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1865/152110) while in subpopulation AFR AF = 0.0422 (1749/41486). AF 95% confidence interval is 0.0405. There are 34 homozygotes in GnomAd4. There are 875 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 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.681-8C>T		splice_region intron	N/A	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.681-8C>T		splice_region intron	N/A	ENSP00000359211.3	Q12882-1
	DPYD	ENST00000876340.1		c.681-8C>T		splice_region intron	N/A	ENSP00000546399.1
	DPYD	ENST00000969915.1		c.681-8C>T		splice_region intron	N/A	ENSP00000639974.1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1861 AN: 151992 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0422

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00505

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00307 AC: 771 AN: 251156 AF XY: 0.00222

Gnomad AFR exome AF: 0.0410

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00139 AC: 2024 AN: 1460198 Hom.: 44 Cov.: 29 AF XY: 0.00119 AC XY: 866 AN XY: 726498

African (AFR) AF: 0.0476 AC: 1591 AN: 33420

American (AMR) AF: 0.00208 AC: 93 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5756

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1110710

Other (OTH) AF: 0.00331 AC: 200 AN: 60332

GnomAD4 genome AF: 0.0123 AC: 1865 AN: 152110 Hom.: 34 Cov.: 32 AF XY: 0.0118 AC XY: 875 AN XY: 74376

African (AFR) AF: 0.0422 AC: 1749 AN: 41486

American (AMR) AF: 0.00504 AC: 77 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67982

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00877 Hom.: 20

Bravo AF: 0.0135

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Dihydropyrimidine dehydrogenase deficiency (2)
-	-	2	not provided (2)
-	-	1	DPYD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.75
DANN	Benign	0.26
PhyloP100		-0.056
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0040
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: rs74774246; hg19: chr1-98157362;