rs72549304

Variant names:

• chr1-97549609-G-A
• rs72549304
• NM_000110.4:c.1475C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-97549609-G-A
• chr1-97549609-G-C
• chr1-97549609-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: DPYD NM_000110.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 9.53
• Publications: 17 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: Likely_pathogenic. The variant received 9 ACMG points.

• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 298293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYD	NM_000110.4	c.1475C>T	p.Ser492Leu	missense_variant	Exon 12 of 23	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8	c.1475C>T	p.Ser492Leu	missense_variant	Exon 12 of 23	1	NM_000110.4	ENSP00000359211.3

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

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251052 AF XY: 0.0000590

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 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

African (AFR) AF: 0.000120 AC: 4 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111830

Other (OTH) AF: 0.0000331 AC: 2 AN: 60374

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

African (AFR) AF: 0.000121 AC: 5 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000708 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency Pathogenic:4 Uncertain:1

-

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 09, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (gnomAD). This frequency is not significantly higher than estimated 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 homozygous individuals affected with Dihydropyrimidine Dehydrogenase Deficiency (e.g. Van Kuilenburg_2002, Cheema_2020). 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 is likely to be associated with disease. Publications report experimental evidence evaluating an impact on protein function, finding that the variant resulted in nearly absent enzyme activity in homozygous patient cells and substantially reduced activity (~18% of wild type) when expressed in an isogenic cell line (e.g. Van Kuilenburg_2002, Offer_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24648345, 11988088, 24590654, 31745289, 32707991, 32899374, 28481884, 12912951, 27454530, 17046731, 33083013). ClinVar contains an entry for this variant (Variation ID: 298293). Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 08, 2022

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (C>T) which results in a serine to leucine amino acid change at residue 492 of the DPYD protein. This is a previously reported variant (ClinVar) which has been reported in homozygous state in an individual with complete dihydropyrimidine dehydrogese deficiency (PMID: 11988088) and in heterozygous state in an individual with grade 4 toxicity to capecitabine (PMID: 28481884). This variant is rare in the gnomAD control population dataset (13/282442 alleles or 0.005%). Multiple bioinformatic tools predict that this serine to leucine amino acid change will be damaging, and serine is highly conserved at this protein position in vertebrates. Functiol studies suggest that the variant protein has significantly decreased dihydropyrimidine dehydrogese activity decreased compared to wild-type protein (PMID: 11988088, 24648345). Ser492 is in the FAD cofactor binding site, and protein crystal structure alysis suggests that substituting leucine at this position inhibits FAD interaction (PMID: 11988088). Given the available evidence, we consider this variant to be likely pathogenic. ACMG Criteria: PM2, PP3, PS3 -

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
PhyloP100		9.5
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
Mutation Taster		=32/68	disease causing (ClinVar)

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