rs763615602

Positions:

chr2-73927047-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_080916.3(DGUOK):c.137A>G(p.Asn46Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000168 in 1,608,694 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 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

DGUOK
NM_080916.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.76

Variant links:

Genes affected

DGUOK (HGNC:2858): (deoxyguanosine kinase) In mammalian cells, the phosphorylation of purine deoxyribonucleosides is mediated predominantly by two deoxyribonucleoside kinases, cytosolic deoxycytidine kinase and mitochondrial deoxyguanosine kinase. The protein encoded by this gene is responsible for phosphorylation of purine deoxyribonucleosides in the mitochondrial matrix. In addition, this protein phosphorylates several purine deoxyribonucleoside analogs used in the treatment of lymphoproliferative disorders, and this phosphorylation is critical for the effectiveness of the analogs. Alternative splice variants encoding different protein isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

DGUOK links:

DGUOK (HGNC:):

DGUOK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

PP5

Variant 2-73927047-A-G is Pathogenic according to our data. Variant chr2-73927047-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 253062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DGUOK	NM_080916.3 linkuse as main transcript	c.137A>G	p.Asn46Ser	missense_variant	1/7	ENST00000264093.9	NP_550438.1	Q16854-1E5KSL5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DGUOK	ENST00000264093.9 linkuse as main transcript	c.137A>G	p.Asn46Ser	missense_variant	1/7	1	NM_080916.3	ENSP00000264093.4		Q16854-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152256

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000246

AC:

AN:

243554

Hom.:

AF XY:

0.00000754

AC XY:

AN XY:

132676

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000448

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1456438

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

724830

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 46 of the DGUOK protein (p.Asn46Ser). This variant is present in population databases (rs763615602, gnomAD 0.006%). This missense change has been observed in individuals with a spectrum of autosomal recessive mitochondrial disorders (PMID: 17073823, 17452231, 18205204, 23043144, 26874653). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 253062). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DGUOK protein function. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18825706, 29137425, 17073823, 18205204, 23043144, 17452231, 26874653, 23968935, 34426522, 31589614, 30956829, 37718732, 35690264, 37830057, 32278775) -

Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2007

- -

Portal hypertension, noncirrhotic, 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2007

- -

Portal hypertension, noncirrhotic

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Mar 31, 2016

- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

.;D;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;H;H

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.9

.;D;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0030

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.99

.;D;.

Vest4

0.79

MutPred

0.88

Gain of glycosylation at N46 (P = 0.0407);Gain of glycosylation at N46 (P = 0.0407);Gain of glycosylation at N46 (P = 0.0407);

MVP

0.96

MPC

0.40

ClinPred

0.98

GERP RS

4.2

Varity_R

0.93

gMVP

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over