rs141044036

Positions:

• chr1-97082365-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The ENST00000370192.8(DPYD):​c.2872A>G​(p.Lys958Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: DPYD ENST00000370192.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.82

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain 4Fe-4S ferredoxin-type 2 (size 32) in uniprot entity DPYD_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in ENST00000370192.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYD	NM_000110.4	c.2872A>G	p.Lys958Glu	missense_variant	22/23	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8	c.2872A>G	p.Lys958Glu	missense_variant	22/23	1	NM_000110.4	ENSP00000359211	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251256 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135788

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461368 Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15 AN XY: 726992

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 17, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 04, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	0.56	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.75
MVP		0.98
MPC		0.41
ClinPred		0.77	D
GERP RS		5.8
Varity_R		0.63
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs141044036; hg19: chr1-97547921;