chr1-97078076-A-G

Variant names:

• chr1-97078076-A-G
• rs17470762
• NM_000110.4:c.*900T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000110.4(DPYD):​c.*900T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0261 in 152,272 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.026 (93 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: DPYD NM_000110.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 0.316
• Publications: 5 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

ENSG00000296260 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-97078076-A-G is Benign according to our data. Variant chr1-97078076-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 100063.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0261 (3972/152272) while in subpopulation NFE AF = 0.0339 (2308/68012). AF 95% confidence interval is 0.0328. There are 93 homozygotes in GnomAd4. There are 2056 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 93 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYD	NM_000110.4	c.*900T>C		3_prime_UTR_variant	Exon 23 of 23	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8	c.*900T>C		3_prime_UTR_variant	Exon 23 of 23	1	NM_000110.4	ENSP00000359211.3
ENSG00000296260	ENST00000737657.1	n.550-3671A>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3975 AN: 152154 Hom.: 94 Cov.: 33

Gnomad AFR AF: 0.00615

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0980

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0340

Gnomad OTH AF: 0.0211

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0261 AC: 3972 AN: 152272 Hom.: 93 Cov.: 33 AF XY: 0.0276 AC XY: 2056 AN XY: 74448

African (AFR) AF: 0.00613 AC: 255 AN: 41580

American (AMR) AF: 0.0152 AC: 232 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4828

European-Finnish (FIN) AF: 0.0980 AC: 1039 AN: 10598

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0339 AC: 2308 AN: 68012

Other (OTH) AF: 0.0209 AC: 44 AN: 2110

Alfa AF: 0.0278 Hom.: 143

Bravo AF: 0.0188

Asia WGS AF: 0.00318 AC: 11 AN: 3472

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Other:1

-

Diasio Lab, Mayo Clinic

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.76
PhyloP100		0.32
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: rs17470762; hg19: chr1-97543632;