rs104893633

Variant names:

• chr2-73958201-G-T
• rs104893633
• NM_080916.3:c.763G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_080916.3(DGUOK):​c.763G>T​(p.Asp255Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,546 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DGUOK NM_080916.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.47
• Publications: 4 publications found

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

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 2-73958201-G-T is Pathogenic according to our data. Variant chr2-73958201-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 8159.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080916.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGUOK	NM_080916.3	MANE Select	c.763G>T	p.Asp255Tyr	missense	Exon 6 of 7	NP_550438.1
	DGUOK	NM_080918.3		c.499G>T	p.Asp167Tyr	missense	Exon 4 of 5	NP_550440.1
	DGUOK	NM_001318859.2		c.481G>T	p.Asp161Tyr	missense	Exon 4 of 5	NP_001305788.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGUOK	ENST00000264093.9	TSL:1 MANE Select	c.763G>T	p.Asp255Tyr	missense	Exon 6 of 7	ENSP00000264093.4
	DGUOK	ENST00000418996.5	TSL:1	n.*116G>T		non_coding_transcript_exon	Exon 3 of 4	ENSP00000408209.1
	DGUOK	ENST00000629438.2	TSL:1	c.*380G>T		3_prime_UTR	Exon 5 of 6	ENSP00000487122.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251462 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461546 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727106

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111818

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) (1)
1	-	-	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4;C5191055:Mitochondrial DNA depletion syndrome 3 (hepatocerebral type);CN305369:Portal hypertension, noncirrhotic, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.5
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.88		Loss of disorder (P = 0.0213)
MVP		0.98
MPC		0.60
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.64
Mutation Taster		=22/78	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104893633; hg19: chr2-74185328;