rs72549307

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000110.4(DPYD):c.632A>G(p.Tyr211Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,538 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

DPYD
NM_000110.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4

Conservation

PhyloP100: 7.56

Publications

9 publications found

Variant links:

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

DPYD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 1-97699399-T-C is Pathogenic according to our data. Variant chr1-97699399-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 554571.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYD	NM_000110.4 link	c.632A>G	p.Tyr211Cys	missense_variant	Exon 6 of 23	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8 link	c.632A>G	p.Tyr211Cys	missense_variant	Exon 6 of 23	1	NM_000110.4	ENSP00000359211.3
DPYD	ENST00000474241.1 link	n.396A>G		non_coding_transcript_exon_variant	Exon 3 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152030

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251200

AF XY:

0.00000737

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461508

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727062

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111702

Other (OTH)

AF:

0.0000166

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152030

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dihydropyrimidine dehydrogenase deficiency

Pathogenic:1Uncertain:2

Apr 11, 2023

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 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. -

Nov 28, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Aug 10, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DPYD c.632A>G (p.Tyr211Cys) 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 4e-06 in 251200 control chromosomes (gnomAD). The variant, c.632A>G, has been reported in the literature in a homozygous individual affected with milder form of childhood onset Dihydropyrimidine Dehydrogenase Deficiency (van Kuilenburg 2002), this individual had very low (almost undetectable) enzyme activity measured from fibroblasts; however, the sequencing technology utilized in this study didn't exclude the presence of co-occurring (e.g. deep intronic) variants. In addition, the variant was reported in a heterozygous individual affected with severe 5-fluorouracil toxicity following chemotherapy, but was also reported in an individual with low/no toxicity (Froehlich_2015). Finally, a recent report found the variant in a heterozygous individual with low enzyme activity, who underwent DPYD phenotyping by a biochemical assay (namely the 5-FU degradation rate (5-FUDR)) (De Luca_2022). In vitro experimental evidence evaluating an impact on protein function demonstrated that the variant resulted in a decreased enzyme activity, corresponding to about 14% residual activity (Offer_2014). The following publications have been ascertained in the context of this evaluation (PMID: 11988088, 2464834, 24923815, 29152729, 36430399, 35306539 ). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Inborn genetic diseases

Uncertain:1

Jun 08, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.632A>G (p.Y211C) alteration is located in exon 6 (coding exon 6) of the DPYD gene. This alteration results from a A to G substitution at nucleotide position 632, causing the tyrosine (Y) at amino acid position 211 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.31

MutationAssessor

Benign

1.9

PhyloP100

7.6

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-8.2

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MVP

0.96

MPC

0.39

ClinPred

1.0

GERP RS

5.5

Varity_R

0.43

gMVP

0.90

Mutation Taster

=14/86

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over