2-73938978-C-G

Position:

chr2-73938978-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP4_StrongBS1_SupportingBS2

The NM_080916.3(DGUOK):c.211C>G(p.Pro71Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000355 in 1,614,010 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 4 hom. )

Consequence

DGUOK
NM_080916.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8B:1

Conservation

PhyloP100: 7.42

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 Benign. Variant got -8 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 6: BayesDel_addAF, BayesDel_noAF, Cadd, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.0591152).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000341 (499/1461764) while in subpopulation AMR AF= 0.00454 (203/44722). AF 95% confidence interval is 0.00403. There are 4 homozygotes in gnomad4_exome. There are 225 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DGUOK	NM_080916.3 linkuse as main transcript	c.211C>G	p.Pro71Ala	missense_variant	2/7	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.211C>G	p.Pro71Ala	missense_variant	2/7	1	NM_080916.3	ENSP00000264093.4		Q16854-1

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

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:

0.000397

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000879

AC:

221

AN:

251464

Hom.:

AF XY:

0.000721

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00463

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:

0.000290

Gnomad OTH exome

AF:

0.00456

GnomAD4 exome

AF:

0.000341

AC:

499

AN:

1461764

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

225

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00454

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000236

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.000486

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000281

Hom.:

Bravo

AF:

0.000638

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000766

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 09, 2024	BS1, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 21, 2022	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 71 of the DGUOK protein (p.Pro71Ala). This variant is present in population databases (rs184770596, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of mitochondrial DNA depletion syndrome (PMID: 25131622). ClinVar contains an entry for this variant (Variation ID: 208752). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2017	The P71A variant in the DGUOK gene has been reported in the homozygous state in an individual with intellectual disability and spastic quadriplegia, but the publication does not comment on the presence or absence of liver disease (Srivastava et al., 2014). The P71A variant is observed in 65/22564 (0.56%) alleles, although not in the homozygous state, from individuals of Latino background in the ExAC dataset (Lek et al., 2016). The P71A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P71A as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 23, 2023	Variant summary: DGUOK c.211C>G (p.Pro71Ala) results in a non-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 0.00088 in 251464 control chromosomes, predominantly at a frequency of 0.0046 within the Latino subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in DGUOK causing DGUOK-Related Disorders, allowing no conclusion about variant significance. c.211C>G has been reported in the literature in at least one homozygous individual affected with Mitochondrial DNA depletion syndrome, 3 (example: Srivastava_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25131622). Five 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 uncertain significance. -

Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jul 26, 2018

The DGUOK c.211C>G (p.Pro71Ala) variant is a missense variant that has been reported in a homozygous state in one individual with mitochondrial DNA depletion syndrome, type 3 (Srivastava et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.014019 in the Iberian population of the 1000 Genomes Project. The evidence for this variant is limited. The p.Pro71Ala variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for mitochondrial DNA depletion syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2014

There is insufficient or conflicting evidence for classification of this alteration. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 01, 2022

- -

DGUOK-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 23, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.95

D;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.059

T;T

MetaSVM

Uncertain

0.65

MutationAssessor

Pathogenic

3.0

M;M

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-7.6

D;D

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.97

D;.

Vest4

0.84

MVP

1.0

MPC

0.33

ClinPred

0.24

GERP RS

5.3

Varity_R

0.92

gMVP

0.71

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