2-73926924-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_080916.3(DGUOK):c.14G>A(p.Arg5His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,058 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DGUOK NM_080916.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.892

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DGUOK	NM_080916.3	c.14G>A	p.Arg5His	missense_variant	1/7	ENST00000264093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DGUOK	ENST00000264093.9	c.14G>A	p.Arg5His	missense_variant	1/7	1	NM_080916.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461058 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726880

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 31, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.82	T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.43	T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.90	.;P;.
Vest4		0.47
MutPred		0.57		Loss of methylation at R5 (P = 0.002);Loss of methylation at R5 (P = 0.002);Loss of methylation at R5 (P = 0.002);
MVP		0.98
MPC		0.30
ClinPred		0.77	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.14
gMVP		0.64

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: rs775274523; hg19: chr2-74154051;