rs762550967

Variant names:

• chr2-73927040-G-A
• rs762550967
• NM_080916.3:c.130G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-73927040-G-A
• chr2-73927040-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_080916.3(DGUOK):​c.130G>A​(p.Glu44Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,457,026 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: 0.000012 (0 hom.)
• Consequence: DGUOK NM_080916.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.02
• Publications: 5 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 Gene-Disease associations (from GenCC):

• mitochondrial DNA depletion syndrome 3 (hepatocerebral type)

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• portal hypertension, noncirrhotic

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_080916.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 2-73927040-G-A is Pathogenic according to our data. Variant chr2-73927040-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 253066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.130G>A	p.Glu44Lys	missense	Exon 1 of 7	NP_550438.1
	DGUOK	NM_080918.3		c.130G>A	p.Glu44Lys	missense	Exon 1 of 5	NP_550440.1
	DGUOK	NM_001318859.2		c.130G>A	p.Glu44Lys	missense	Exon 1 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.130G>A	p.Glu44Lys	missense	Exon 1 of 7	ENSP00000264093.4
	DGUOK	ENST00000629438.2	TSL:1	c.130G>A	p.Glu44Lys	missense	Exon 1 of 6	ENSP00000487122.1
	DGUOK	ENST00000418996.5	TSL:1	n.130G>A		non_coding_transcript_exon	Exon 1 of 4	ENSP00000408209.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000245 AC: 6 AN: 244436 AF XY: 0.0000225

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: 0.0000268

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1457026 Hom.: 0 Cov.: 32 AF XY: 0.0000152 AC XY: 11 AN XY: 725074

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48636

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111976

Other (OTH) AF: 0.0000331 AC: 2 AN: 60362

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000729 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		4.0
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.85		Gain of methylation at E44 (P = 0.0126)
MVP		0.98
MPC		0.55
ClinPred		0.99	D
GERP RS		4.2
PromoterAI		-0.099	Neutral
Varity_R		0.99
gMVP		0.94
Mutation Taster		=10/90	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: rs762550967; hg19: chr2-74154167;