rs863223949

chr2-73957134-AAG-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_080916.3(DGUOK):c.605_606del(p.Arg202ThrfsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000205 in 1,461,476 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DGUOK NM_080916.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.87

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-73957134-AAG-A is Pathogenic according to our data. Variant chr2-73957134-AAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 214288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DGUOK	NM_080916.3	c.605_606del	p.Arg202ThrfsTer13	frameshift_variant	5/7	ENST00000264093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DGUOK	ENST00000264093.9	c.605_606del	p.Arg202ThrfsTer13	frameshift_variant	5/7	1	NM_080916.3	P1
DGUOK-AS1	ENST00000667561.3	n.308-9201_308-9200del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251360 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461476 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727076

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 14, 2017	The p.Arg202ThrfsX13 (NM_080916.2 c.605_606delGA) variant in DGUOK has been repo rted in 3 compound heterozygous individuals with clinical features of Deoxyguano sine kinase deficiency or mitochondrial DNA depletion syndrome (Ronchi 2012 and Alberio 2007). This variant has also been reported in ClinVar (Variation ID#2142 88) as pathogenic by 1 laboratory. This variant has been identified in 0.002% (2 /11,2150) of European chromosomes by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org). Although this variant has been seen in the gene ral population, its frequency is low enough to be consistent with a recessive ca rrier frequency. This variant is predicted to cause a frameshift, which alters t he protein?s amino acid sequence beginning at position 202 and leads to a premat ure termination codon 13 amino acids downstream. This alteration is then predict ed to lead to a truncated or absent protein. Biallelic loss of function of funct ion of the DGUOK gene is an established disease mechanism in Deoxyguanosine kina se deficiency. In summary, this variant meets criteria to be classified as patho genic for Deoxyguanosine kinase deficiency in an autosomal recessive manner base d upon its occurrence in patients and predicted null effect. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 18, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2019	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30609409, 17280874, 18205204, 23043144, 24478274) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Arg202Thrfs*13) in the DGUOK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DGUOK are known to be pathogenic (PMID: 18205204). This variant is present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with DGUOK-related conditions (PMID: 17280874). This variant is also known as 603-604 delGA (K201fs214X). ClinVar contains an entry for this variant (Variation ID: 214288). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 18, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs863223949; hg19: chr2-74184261;