Genetic Variant NM_080916.3:c.2T>C (chr2-73926912-T-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_SupportingPM2PP5_Moderate

The NM_080916.3(DGUOK):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,138 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: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DGUOK
NM_080916.3 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.94

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 18 codons. Genomic position: 73926962. Lost 0.062 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-73926912-T-C is Pathogenic according to our data. Variant chr2-73926912-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2734235.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DGUOK	NM_080916.3 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	ENST00000264093.9	NP_550438.1	Q16854-1E5KSL5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DGUOK	ENST00000264093.9 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	1	NM_080916.3	ENSP00000264093.4		Q16854-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250520

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135616

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461138

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726924

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Oct 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the DGUOK mRNA. The next in-frame methionine is located at codon 18. This variant is present in population databases (rs757874547, gnomAD 0.003%). Disruption of the initiator codon has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 16263314, 16908739, 32278775, 32793533). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.53

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Benign

0.28

.;T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.99

PROVEAN

Benign

-0.71

.;N;N

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.97

.;D;.

Vest4

0.89

MutPred

1.0

Gain of phosphorylation at M1 (P = 0.053);Gain of phosphorylation at M1 (P = 0.053);Gain of phosphorylation at M1 (P = 0.053);

MVP

1.0

ClinPred

0.99

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.94

gMVP

0.73

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