rs104893632

Positions:

chr2-73957212-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The ENST00000264093.9(DGUOK):c.679G>A(p.Glu227Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,976 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

DGUOK
ENST00000264093.9 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 8.06

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-AS1 (HGNC:43441): (DGUOK antisense RNA 1)

DGUOK-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a chain Deoxyguanosine kinase, mitochondrial (size 237) in uniprot entity DGUOK_HUMAN there are 19 pathogenic changes around while only 3 benign (86%) in ENST00000264093.9

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 2-73957212-G-A is Pathogenic according to our data. Variant chr2-73957212-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73957212-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DGUOK	NM_080916.3 linkuse as main transcript	c.679G>A	p.Glu227Lys	missense_variant	5/7	ENST00000264093.9	NP_550438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DGUOK	ENST00000264093.9 linkuse as main transcript	c.679G>A	p.Glu227Lys	missense_variant	5/7	1	NM_080916.3	ENSP00000264093	P1	Q16854-1
DGUOK-AS1	ENST00000667561.3 linkuse as main transcript	n.308-9277C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152192

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

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251342

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000381

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: 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	GeneDx	Oct 20, 2022	Published functional studies demonstrate a severely decreased catalytic rate (PMID: 14623087); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27324545, 18825706, 17892433, 22494545, 24478274, 28493820, 29137425, 30366773, 12205643, 35488641, 19103789, 32482602, 14623087) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 227 of the DGUOK protein (p.Glu227Lys). This variant is present in population databases (rs104893632, gnomAD 0.01%). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 12205643, 19103789, 27324545, 28493820, 32482602). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8158). 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) performed at Invitae indicates that this missense variant is not expected to disrupt DGUOK protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2002

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.679G>A (p.E227K) alteration is located in exon 5 (coding exon 5) of the DGUOK gene. This alteration results from a G to A substitution at nucleotide position 679, causing the glutamic acid (E) at amino acid position 227 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (6/251342) total alleles studied. This alteration has been reported in the homozygous state or compound heterozygous with a second pathogenic DGUOK variant in trans in patients with mitochondrial DNA depletion syndrome (Deng, 2016; Lee, 2009; Salviati, 2002; Xia, 2020). Experimental studies with recombinant E227K enzyme showed a severely decreased catalytic rate (Wang, 2003). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

DGUOK-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 22, 2024

Variant summary: DGUOK c.679G>A (p.Glu227Lys) results in a conservative amino acid change located in the Deoxynucleoside kinase domain (IPR031314) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251342 control chromosomes (gnomAD). c.679G>A has been reported in the literature in multiple individuals affected with DGUOK-Related Disorders (examples: Salviati_2002,Lee_2009, Deng_2016,Unal_2017, Xia_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 27324545, 12205643, 32482602, 19103789, 28493820). ClinVar contains an entry for this variant (Variation ID: 8158). Based on the evidence outlined above, the variant was classified as pathogenic. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4;C5191055:Mitochondrial DNA depletion syndrome 3 (hepatocerebral type);CN305369:Portal hypertension, noncirrhotic, 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PM2_Supporting+PP3_Strong+PM3_VeryStrong+PP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.93

MutPred

0.96

Gain of methylation at E227 (P = 0.0121);

MVP

0.99

MPC

0.57

ClinPred

0.99

GERP RS

5.0

Varity_R

0.95

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.24

Position offset: 28

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