2-73926914-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 13/21 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:6 O:1
• Conservation: PhyloP100: -0.201

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 193482.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=3, Likely_benign=3, not_provided=1}.
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DGUOK	NM_080916.3	c.4G>T	p.Ala2Ser	missense_variant	1/7	ENST00000264093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DGUOK	ENST00000264093.9	c.4G>T	p.Ala2Ser	missense_variant	1/7	1	NM_080916.3	P1

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 452 AN: 152232 Hom.: 1 Cov.: 33

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

GnomAD3 exomes AF: 0.00255 AC: 639 AN: 250362 Hom.: 3 AF XY: 0.00247 AC XY: 335 AN XY: 135558

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 SAS exome AF: 0.000457

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.: 27 Cov.: 32 AF XY: 0.00482 AC XY: 3501 AN XY: 726856

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000545

Gnomad4 FIN exome AF: 0.0000951

Gnomad4 NFE exome AF: 0.00612

Gnomad4 OTH exome AF: 0.00502

GnomAD4 genome AF: 0.00296 AC: 451 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.00240 AC XY: 179 AN XY: 74502

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00512

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00412 Hom.: 2

Bravo AF: 0.00325

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00234 AC: 284

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00462

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	DGUOK: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 08, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 18, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2020	This variant is associated with the following publications: (PMID: 19748572, 18828154, 22622127, 17073823) -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The DGUOK p.Ala2Ser variant was identified as a compound heterozygous variant in two pediatric cases with mitochondrial DNA depletion syndrome (Mousson_de_Camaret_2007_PMID: 17073823; Buchaklian_2012_PMID: 22622127). The variant was identified in dbSNP (ID: rs147551003) and ClinVar (classified as uncertain significance by Children's Mercy Hospital, GeneDx, Mayo Clinic, EGL Genetic Diagnostics, CeGaT Praxis; and as benign by Invitae and Mendelics). The variant was identified in control databases in 727 of 281762 chromosomes (3 homozygous) at a frequency of 0.00258 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 570 of 128878 chromosomes (freq: 0.004423), Latino in 91 of 35430 chromosomes (freq: 0.002568), Other in 16 of 7212 chromosomes (freq: 0.002219), Ashkenazi Jewish in 11 of 10352 chromosomes (freq: 0.001063), African in 22 of 24908 chromosomes (freq: 0.000883), South Asian in 14 of 30616 chromosomes (freq: 0.000457) and European (Finnish) in 3 of 24434 chromosomes (freq: 0.000123), but was not observed in the East Asian population. The p.Ala2 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) Uncertain:1 Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Uncertain significance and reported on 10/30/2014 by GTR ID 320384. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

DGUOK-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 12, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	12
Dann	Uncertain	0.99
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.52	T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.0	M;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.043	.;B;.
Vest4		0.74
MVP		0.90
MPC		0.15
ClinPred		0.0097	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.058
gMVP		0.55

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: rs147551003; hg19: chr2-74154041;