rs4777

Variant names:

• chr2-73958749-A-T
• rs4777
• ENST00000418996.5:n.*200A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000418996.5(DGUOK):​n.*200A>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 1,605,462 control chromosomes in the GnomAD database, including 283,273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25339 hom., cov: 32)
  • Exomes 𝑓: 0.59 (257934 hom.)
• Consequence: DGUOK ENST00000418996.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.245
• Publications: 20 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 2-73958749-A-T is Benign according to our data. Variant chr2-73958749-A-T is described in ClinVar as Benign. ClinVar VariationId is 137083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DGUOK	NM_080916.3	c.*13A>T		3_prime_UTR_variant	Exon 7 of 7	ENST00000264093.9	NP_550438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DGUOK	ENST00000264093.9	c.*13A>T		3_prime_UTR_variant	Exon 7 of 7	1	NM_080916.3	ENSP00000264093.4

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87200 AN: 151928 Hom.: 25326 Cov.: 32

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.751

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.523

Gnomad EAS AF: 0.516

Gnomad SAS AF: 0.555

Gnomad FIN AF: 0.723

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.558

GnomAD2 exomes AF: 0.588 AC: 147753 AN: 251346 AF XY: 0.589

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.560

Gnomad ASJ exome AF: 0.529

Gnomad EAS exome AF: 0.533

Gnomad FIN exome AF: 0.719

Gnomad NFE exome AF: 0.605

Gnomad OTH exome AF: 0.583

GnomAD4 exome AF: 0.594 AC: 862808 AN: 1453416 Hom.: 257934 Cov.: 32 AF XY: 0.592 AC XY: 428634 AN XY: 723490

African (AFR) AF: 0.498 AC: 16591 AN: 33314

American (AMR) AF: 0.561 AC: 25088 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 13628 AN: 26082

East Asian (EAS) AF: 0.480 AC: 19055 AN: 39672

South Asian (SAS) AF: 0.563 AC: 48486 AN: 86104

European-Finnish (FIN) AF: 0.711 AC: 37995 AN: 53402

Middle Eastern (MID) AF: 0.522 AC: 3004 AN: 5754

European-Non Finnish (NFE) AF: 0.601 AC: 664191 AN: 1104288

Other (OTH) AF: 0.579 AC: 34770 AN: 60092

GnomAD4 genome AF: 0.574 AC: 87249 AN: 152046 Hom.: 25339 Cov.: 32 AF XY: 0.580 AC XY: 43093 AN XY: 74318

African (AFR) AF: 0.510 AC: 21128 AN: 41468

American (AMR) AF: 0.555 AC: 8484 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 1814 AN: 3466

East Asian (EAS) AF: 0.516 AC: 2663 AN: 5162

South Asian (SAS) AF: 0.556 AC: 2675 AN: 4814

European-Finnish (FIN) AF: 0.723 AC: 7636 AN: 10566

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.601 AC: 40849 AN: 67974

Other (OTH) AF: 0.556 AC: 1171 AN: 2106

Alfa AF: 0.590 Hom.: 4928

Bravo AF: 0.557

Asia WGS AF: 0.551 AC: 1916 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 27, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Portal hypertension, noncirrhotic Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	5.3
DANN	Benign	0.79
PhyloP100		-0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs4777; hg19: chr2-74185876; COSMIC: COSV51203699; COSMIC: COSV51203699;