Genetic Variant TK1:p.Glu74Glu (chr17-78182670-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_003258.5(TK1):c.222G>A(p.Glu74Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0341 in 1,579,492 control chromosomes in the GnomAD database, including 2,570 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.034 ( 252 hom., cov: 32)

Exomes 𝑓: 0.034 ( 2318 hom. )

Consequence

TK1
NM_003258.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.337

Publications

10 publications found

Variant links:

Genes affected

TK1 (HGNC:11830): (thymidine kinase 1) The protein encoded by this gene is a cytosolic enzyme that catalyzes the addition of a gamma-phosphate group to thymidine. This creates dTMP and is the first step in the biosynthesis of dTTP, which is one component required for DNA replication. The encoded protein, whose levels fluctuate depending on the cell cycle stage, can act as a low activity dimer or a high activity tetramer. High levels of this protein have been used as a biomarker for diagnosing and categorizing many types of cancers. [provided by RefSeq, Oct 2016]

TK1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP7

Synonymous conserved (PhyloP=-0.337 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TK1	NM_003258.5 link	c.222G>A	p.Glu74Glu	synonymous_variant	Exon 4 of 7	ENST00000301634.12	NP_003249.3	P04183A0A384MDV9
TK1	NM_001363848.1 link	c.222G>A	p.Glu74Glu	synonymous_variant	Exon 4 of 6		NP_001350777.1
TK1	NM_001346663.2 link	c.222G>A	p.Glu74Glu	synonymous_variant	Exon 4 of 7		NP_001333592.1	K7ES52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TK1	ENST00000301634.12 link	c.222G>A	p.Glu74Glu	synonymous_variant	Exon 4 of 7	1	NM_003258.5	ENSP00000301634.6		P04183

Frequencies

GnomAD3 genomes

AF:

0.0342

AC:

5198

AN:

152112

Hom.:

252

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0166

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0508

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.234

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.0278

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0234

Gnomad OTH

AF:

0.0335

GnomAD2 exomes

AF:

0.0589

AC:

12024

AN:

204050

AF XY:

0.0604

show subpopulations

Gnomad AFR exome

AF:

0.0160

Gnomad AMR exome

AF:

0.0781

Gnomad ASJ exome

AF:

0.0153

Gnomad EAS exome

AF:

0.239

Gnomad FIN exome

AF:

0.0257

Gnomad NFE exome

AF:

0.0246

Gnomad OTH exome

AF:

0.0459

GnomAD4 exome

AF:

0.0341

AC:

48672

AN:

1427262

Hom.:

2318

Cov.:

AF XY:

0.0365

AC XY:

25815

AN XY:

707940

show subpopulations

African (AFR)

AF:

0.0176

AC:

577

AN:

32868

American (AMR)

AF:

0.0784

AC:

3102

AN:

39562

Ashkenazi Jewish (ASJ)

AF:

0.0145

AC:

371

AN:

25600

East Asian (EAS)

AF:

0.249

AC:

9537

AN:

38280

South Asian (SAS)

AF:

0.109

AC:

8944

AN:

82010

European-Finnish (FIN)

AF:

0.0246

AC:

1120

AN:

45518

Middle Eastern (MID)

AF:

0.0669

AC:

382

AN:

5712

European-Non Finnish (NFE)

AF:

0.0202

AC:

22204

AN:

1098450

Other (OTH)

AF:

0.0411

AC:

2435

AN:

59262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

1834

3669

5503

7338

9172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1016

2032

3048

4064

5080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0342

AC:

5201

AN:

152230

Hom.:

252

Cov.:

AF XY:

0.0369

AC XY:

2747

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0167

AC:

694

AN:

41564

American (AMR)

AF:

0.0506

AC:

774

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

AN:

3470

East Asian (EAS)

AF:

0.234

AC:

1204

AN:

5144

South Asian (SAS)

AF:

0.105

AC:

505

AN:

4820

European-Finnish (FIN)

AF:

0.0278

AC:

295

AN:

10610

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0234

AC:

1591

AN:

68018

Other (OTH)

AF:

0.0345

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

245

491

736

982

1227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0315

Hom.:

151

Bravo

AF:

0.0363

Asia WGS

AF:

0.154

AC:

534

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

4.7

(source)

DANN

Benign

0.86

PhyloP100

-0.34

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over