rs61758444

Variant names:

• chr8-104392804-G-A
• rs61758444
• NM_001385.3:c.1423C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-104392804-G-A
• chr8-104392804-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001385.3(DPYS):​c.1423C>T​(p.Arg475*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: DPYS NM_001385.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.82
• Publications: 7 publications found

Genes affected

DPYS (HGNC:3013): (dihydropyrimidinase) Dihydropyrimidinase catalyzes the conversion of 5,6-dihydrouracil to 3-ureidopropionate in pyrimidine metabolism. Dihydropyrimidinase is expressed at a high level in liver and kidney as a major 2.5-kb transcript and a minor 3.8-kb transcript. Defects in the DPYS gene are linked to dihydropyrimidinuria. [provided by RefSeq, Jul 2008]

DPYS Gene-Disease associations (from GenCC):

• dihydropyrimidinuria

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 8-104392804-G-A is Pathogenic according to our data. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-104392804-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 446083.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
DPYS	NM_001385.3	c.1423C>T	p.Arg475*	stop_gained	Exon 8 of 10	ENST00000351513.7	NP_001376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYS	ENST00000351513.7	c.1423C>T	p.Arg475*	stop_gained	Exon 8 of 10	1	NM_001385.3	ENSP00000276651.2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000135 AC: 34 AN: 251044 AF XY: 0.000192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000127 AC: 186 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.000150 AC XY: 109 AN XY: 727220

African (AFR) AF: 0.0000598 AC: 2 AN: 33472

American (AMR) AF: 0.000201 AC: 9 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.000144 AC: 160 AN: 1111982

Other (OTH) AF: 0.000149 AC: 9 AN: 60396

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74284

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.000131 AC: 2 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.000136

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg475*) in the DPYS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DPYS are known to be pathogenic (PMID: 20362666). This variant is present in population databases (rs61758444, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with dihydropyrimidinuria (PMID: 20362666). ClinVar contains an entry for this variant (Variation ID: 446083). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects DPYS function (PMID: 20362666, 28642038). For these reasons, this variant has been classified as Pathogenic. -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies found this variant is associated with significantly reduced enzyme activity and reduced protein stability (PMID: 20362666, 28642038); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 45 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 25525159, 31589614, 28642038, 34426522, 20362666) -

Dihydropyrimidinase deficiency Pathogenic:3

Oct 08, 2021

New York Genome Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 05, 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: DPYS c.1423C>T (p.Arg475X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00014 in 251044 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DPYS causing Dihydropyrimidinase Deficiency, allowing no conclusion about variant significance. c.1423C>T has been reported in the literature in at least one homozygous individual affected with Dihydropyrimidinase Deficiency (e.g. vanKuilenburg_2010). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity (e.g. vanKuilenburg_2010). ClinVar contains an entry for this variant (Variation ID: 446083). Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		1.8
Vest4		0.35
ClinPred		0.82	D
GERP RS		5.1
PromoterAI		-0.068	Neutral
Mutation Taster		=13/187	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: rs61758444; hg19: chr8-105405032; COSMIC: COSV60906407;