rs1801159

chr1-97515839-T-Achr1-97515839-T-Cchr1-97515839-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000110.4(DPYD):c.1627A>T(p.Ile543Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I543V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DPYD NM_000110.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.40

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19106087).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPYD	NM_000110.4	c.1627A>T	p.Ile543Leu	missense_variant	13/23	ENST00000370192.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPYD	ENST00000370192.8	c.1627A>T	p.Ile543Leu	missense_variant	13/23	1	NM_000110.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	12
Dann	Benign	0.94
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.88
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.10
Sift	Benign	0.20	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.58		Loss of methylation at K541 (P = 0.0631);
MVP		0.40
MPC		0.055
ClinPred		0.11	T
GERP RS		-3.1
Varity_R		0.085
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-97981395;