Genetic Variant DGUOK:p.Ala2Ser (chr2-73926914-G-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_080916.3(DGUOK):c.4G>T(p.Ala2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00482 in 1,613,382 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0050 ( 27 hom. )

Consequence

DGUOK
NM_080916.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:6O:1

Conservation

PhyloP100: -0.201

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial DNA depletion syndrome 3 (hepatocerebral type)
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
portal hypertension, noncirrhotic
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

DGUOK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0109478235).

BP6

Variant 2-73926914-G-T is Benign according to our data. Variant chr2-73926914-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193482.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00296 (451/152350) while in subpopulation NFE AF = 0.00512 (348/68010). AF 95% confidence interval is 0.00467. There are 1 homozygotes in GnomAd4. There are 179 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 27 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080916.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DGUOK	NM_080916.3	MANE Select	c.4G>T	p.Ala2Ser	missense	Exon 1 of 7	NP_550438.1	E5KSL5
DGUOK	NM_080918.3		c.4G>T	p.Ala2Ser	missense	Exon 1 of 5	NP_550440.1	Q16854-2
DGUOK	NM_001318859.2		c.4G>T	p.Ala2Ser	missense	Exon 1 of 5	NP_001305788.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DGUOK	ENST00000264093.9	TSL:1 MANE Select	c.4G>T	p.Ala2Ser	missense	Exon 1 of 7	ENSP00000264093.4	Q16854-1
DGUOK	ENST00000418996.5	TSL:1	n.4G>T		non_coding_transcript_exon	Exon 1 of 4	ENSP00000408209.1	Q16854-6
DGUOK	ENST00000893377.1		c.4G>T	p.Ala2Ser	missense	Exon 1 of 7	ENSP00000563436.1

Frequencies

GnomAD3 genomes

AF:

0.00297

AC:

452

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00513

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.00255

AC:

639

AN:

250362

AF XY:

0.00247

show subpopulations

Gnomad AFR exome

AF:

0.000865

Gnomad AMR exome

AF:

0.00260

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000143

Gnomad NFE exome

AF:

0.00435

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00501

AC:

7327

AN:

1461032

Hom.:

Cov.:

AF XY:

0.00482

AC XY:

3501

AN XY:

726856

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33478

American (AMR)

AF:

0.00248

AC:

111

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000727

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000545

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000951

AC:

AN:

52580

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00612

AC:

6805

AN:

1112000

Other (OTH)

AF:

0.00502

AC:

303

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

465

931

1396

1862

2327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

286

572

858

1144

1430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00296

AC:

451

AN:

152350

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

179

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

41584

American (AMR)

AF:

0.00268

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00512

AC:

348

AN:

68010

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00393

Hom.:

Bravo

AF:

0.00325

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00442

AC:

ExAC

AF:

0.00234

AC:

284

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00518

EpiControl

AF:

0.00462

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (10)

Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) (3)

DGUOK-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.52

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.52

MutationAssessor

Uncertain

2.0

PhyloP100

-0.20

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.12

REVEL

Benign

0.23

Sift

Benign

0.053

Sift4G

Benign

0.14

Polyphen

0.043

Vest4

0.74

MVP

0.90

MPC

0.15

ClinPred

0.0097

GERP RS

1.2

PromoterAI

-0.21

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.058

gMVP

0.55

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over