1-97549544-G-T

Variant names:

• chr1-97549544-G-T
• rs199469537
• NM_000110.4:c.1524+16C>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000110.4(DPYD):​c.1524+16C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000894 in 1,613,334 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (1 hom.)
• Consequence: DPYD NM_000110.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.106
• Publications: 2 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-97549544-G-T is Benign according to our data. Variant chr1-97549544-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 100096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000936 (1367/1461068) while in subpopulation NFE AF = 0.00118 (1314/1111432). AF 95% confidence interval is 0.00113. There are 1 homozygotes in GnomAdExome4. There are 661 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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.1524+16C>A		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.1524+16C>A		intron	N/A	ENSP00000359211.3	Q12882-1
	DPYD	ENST00000876340.1		c.1692+16C>A		intron	N/A	ENSP00000546399.1
	DPYD	ENST00000969915.1		c.1524+16C>A		intron	N/A	ENSP00000639974.1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000355 AC: 89 AN: 250726 AF XY: 0.000347

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000716

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000936 AC: 1367 AN: 1461068 Hom.: 1 Cov.: 31 AF XY: 0.000909 AC XY: 661 AN XY: 726854

African (AFR) AF: 0.000179 AC: 6 AN: 33454

American (AMR) AF: 0.0000671 AC: 3 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00118 AC: 1314 AN: 1111432

Other (OTH) AF: 0.000696 AC: 42 AN: 60342

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74440

African (AFR) AF: 0.000144 AC: 6 AN: 41566

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000688 Hom.: 0

Bravo AF: 0.000499

ClinVar

ClinVar submissions

Significance: Likely 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	-0.83
CADD	Benign	1.2
DANN	Benign	0.61
PhyloP100		-0.11
Mutation Taster		=100/0	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: rs199469537; hg19: chr1-98015100;