rs886037846

Positions:

• chr2-73958235-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_080916.3(DGUOK):​c.797T>G​(p.Leu266Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,624 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L266F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DGUOK NM_080916.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.43

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

ACMG classification

Verdict is Pathogenic. Variant got 10 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 2-73958235-T-G is Pathogenic according to our data. Variant chr2-73958235-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 253063.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-73958235-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DGUOK	NM_080916.3	c.797T>G	p.Leu266Arg	missense_variant	6/7	ENST00000264093.9
DGUOK-AS1	NR_104030.1	n.306-28A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DGUOK	ENST00000264093.9	c.797T>G	p.Leu266Arg	missense_variant	6/7	1	NM_080916.3	P1
DGUOK-AS1	ENST00000667561.3	n.308-10300A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460624 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726686

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2007

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 27, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 253063). This missense change has been observed in individual(s) with mtDNA depletion syndrome (PMID: 16263314, 17073823). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 266 of the DGUOK protein (p.Leu266Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.1	D;N
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.91		Gain of disorder (P = 0.0103);.;
MVP		1.0
MPC		0.65
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.80

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

Other links and lift over

dbSNP: rs886037846; hg19: chr2-74185362;