rs72549304

chr1-97549609-G-Achr1-97549609-G-Cchr1-97549609-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000110.4(DPYD):c.1475C>T(p.Ser492Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,686 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: DPYD NM_000110.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 9.53

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837
• PP5: Variant 1-97549609-G-A is Pathogenic according to our data. Variant chr1-97549609-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 298293.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPYD	NM_000110.4	c.1475C>T	p.Ser492Leu	missense_variant	12/23	ENST00000370192.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPYD	ENST00000370192.8	c.1475C>T	p.Ser492Leu	missense_variant	12/23	1	NM_000110.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251052 Hom.: 0 AF XY: 0.0000590 AC XY: 8 AN XY: 135680

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461600 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 727084

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74270

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000619 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency Pathogenic:3 Uncertain:2

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The DPYD c.1475C>T (p.Ser492Leu) missense variant has been reported in one study in which it was found in one individual with dihydropyrimidine dehydrogenase deficiency in a homozygous state (van Kuilenburg et al. 2002). Control data are unavailable for this variant, which is reported at a frequency of 0.00048 in the African population of the Exome Aggregation Consortium. Expression studies showed that the variant resulted in a dramatic reduction in the capacity of the variant enzyme to convert 5-FU to dihydrofluorouracil, the product of DPD catabolism, compared to wild type (Offer et al. 2014). Analysis of the crystal structure showed that the serine residue is located in the binding site for the cofactor FAD and therefore the p.Ser492Leu variant is likely to interfere with cofactor binding due to the substitution of the larger leucine residue with a hydrophobic side-chain. The clinical evidence for this variant is limited. The p.Ser492Leu variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for dihydropyrimidine dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 09, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 23, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2021	Variant summary: DPYD c.1475C>T (p.Ser492Leu) results in a non-conservative amino acid change located in the FAD/NAD(P)-binding domain (IPR023753) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251052 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency (4.4e-05 vs 0.0025), allowing no conclusion about variant significance. c.1475C>T has been reported in the literature in a homozygous state in at least one individual affected with pediatric Dihydropyrimidine Dehydrogenase Deficiency (e.g. Van Kuilenburg_2002). The variant has also been reported as heterozygous in at least one individual who exhibited signs of toxicity upon treatment with capecitabine (e.g. Milano_2016, Etienee-Grimaldi_2017). These data indicate that the variant may be associated with disease. Experimental evidence showed that the variant resulted in significantly reduced enzyme activity in both patient cells and when expressed in an isogenic cell line (e.g. Van Kuilenburg_2002, Offer_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.94
MVP		0.98
MPC		0.29
ClinPred		0.83	D
GERP RS		6.2
Varity_R		0.58
gMVP		0.96

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: rs72549304; hg19: chr1-98015165; COSMIC: COSV64594416; COSMIC: COSV64594416;