rs763706988

Positions:

chr2-73958199-A-ATGAT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_080916.3(DGUOK):c.763_766dup(p.Phe256Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

DGUOK
NM_080916.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: -1.01

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 Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0875 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-73958199-A-ATGAT is Pathogenic according to our data. Variant chr2-73958199-A-ATGAT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DGUOK	NM_080916.3 linkuse as main transcript	c.763_766dup	p.Phe256Ter	frameshift_variant	6/7	ENST00000264093.9	NP_550438.1
DGUOK-AS1	NR_104030.1 linkuse as main transcript	n.313_314insATCA		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DGUOK	ENST00000264093.9 linkuse as main transcript	c.763_766dup	p.Phe256Ter	frameshift_variant	6/7	1	NM_080916.3	ENSP00000264093	P1	Q16854-1
DGUOK-AS1	ENST00000667561.3 linkuse as main transcript	n.308-10265_308-10264insATCA		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251464

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

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:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461612

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jul 25, 2022	ACMG classification criteria: PVS1 strong, PS4 moderated, PM2 moderated, PM3 moderated -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2017	The c.763_766dupGATT pathogenic variant in the DGUOK gene has been reported previously in association with mitochondrial depletion syndrome in several unrelated individuals who were homozygous for c.763_766dupGATT or heterozygous for c.763_766dupGATT and another variant in the DGUOK gene (Mancuso et al., 2003; Dimmock et al., 2008; Villarroya et al., 2009Al-Hussaini et al., 2014). Fibroblasts from an individual homozygous for this variant showed 1-2.6% enzyme activity compared to controls (Mousson et al., 2007). The c.763_766dupGATT variant results in the normal codon, Phenylalanine 256, being replaced by a Stop codon, denoted p.F256X. This pathogenic variant is predicted to cause loss of normal protein function through protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	This sequence change creates a premature translational stop signal (p.Phe256*) in the DGUOK gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 22 amino acid(s) of the DGUOK protein. This variant is present in population databases (rs763706988, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 14568816, 16263314, 17073823, 18205204, 19265691, 24321534). This variant is also known as c.796insTGAT. ClinVar contains an entry for this variant (Variation ID: 8155). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 02, 2021	- -

DGUOK-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 25, 2023

Variant summary: DGUOK c.763_766dupGATT (p.Phe256X), also referred to as c.796insTGAT in the literature, results in a premature termination codon and although nonsense mediated decay is not expected, it is predicted to cause a truncation of the encoded protein, a commonly known mechanism for disease. The variant allele was found at a frequency of 2e-05 in 251464 control chromosomes (gnomAD). c.763_766dupGATT has been reported in the literature as a biallelic genotype in individuals affected with DGUOK-Related Disorders including mitochondrial DNA depletion syndrome (e.g. Slama_2005, Mousson de Camaret_2007, Dimmock_2008). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant results in <5% of normal activity (e.g. Mousson de Camaret_2007). The following publications have been ascertained in the context of this evaluation (PMID: 18205204, 17073823, 16263314). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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