rs74874677

Positions:

chr2-73950650-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_080916.3(DGUOK):c.509A>G(p.Gln170Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,614,182 control chromosomes in the GnomAD database, including 361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 23 hom., cov: 32)

Exomes 𝑓: 0.020 ( 338 hom. )

Consequence

DGUOK
NM_080916.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:11

Conservation

PhyloP100: 9.06

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 Benign. Variant got -18 ACMG points.

PM1

In a chain Deoxyguanosine kinase, mitochondrial (size 237) in uniprot entity DGUOK_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_080916.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0117305815).

BP6

Variant 2-73950650-A-G is Benign according to our data. Variant chr2-73950650-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 137082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73950650-A-G is described in Lovd as [Likely_benign]. Variant chr2-73950650-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0145 (2207/152328) while in subpopulation NFE AF= 0.0218 (1484/68032). AF 95% confidence interval is 0.0209. There are 23 homozygotes in gnomad4. There are 1073 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DGUOK	NM_080916.3 linkuse as main transcript	c.509A>G	p.Gln170Arg	missense_variant	4/7	ENST00000264093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DGUOK	ENST00000264093.9 linkuse as main transcript	c.509A>G	p.Gln170Arg	missense_variant	4/7	1	NM_080916.3	P1	Q16854-1
DGUOK-AS1	ENST00000667561.3 linkuse as main transcript	n.308-2715T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0145

AC:

2206

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00704

Gnomad FIN

AF:

0.0218

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0218

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.0149

AC:

3757

AN:

251484

Hom.:

AF XY:

0.0151

AC XY:

2047

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00406

Gnomad AMR exome

AF:

0.0109

Gnomad ASJ exome

AF:

0.00764

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00918

Gnomad FIN exome

AF:

0.0241

Gnomad NFE exome

AF:

0.0204

Gnomad OTH exome

AF:

0.0174

GnomAD4 exome

AF:

0.0196

AC:

28587

AN:

1461854

Hom.:

338

Cov.:

AF XY:

0.0192

AC XY:

13937

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00332

Gnomad4 AMR exome

AF:

0.0117

Gnomad4 ASJ exome

AF:

0.00800

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00912

Gnomad4 FIN exome

AF:

0.0237

Gnomad4 NFE exome

AF:

0.0221

Gnomad4 OTH exome

AF:

0.0177

GnomAD4 genome

AF:

0.0145

AC:

2207

AN:

152328

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1073

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00409

Gnomad4 AMR

AF:

0.0142

Gnomad4 ASJ

AF:

0.00806

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00704

Gnomad4 FIN

AF:

0.0218

Gnomad4 NFE

AF:

0.0218

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0184

Hom.:

Bravo

AF:

0.0138

TwinsUK

AF:

0.0262

AC:

ALSPAC

AF:

0.0221

AC:

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.0222

AC:

191

ExAC

AF:

0.0153

AC:

1857

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0201

EpiControl

AF:

0.0204

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Uncertain:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	DGUOK: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 18, 2016

- -

Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.012

MetaSVM

Uncertain

0.57

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.82

Sift

Uncertain

0.018

Sift4G

Benign

0.093

Polyphen

1.0

Vest4

0.32

MPC

0.56

ClinPred

0.032

GERP RS

5.7

Varity_R

0.85

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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