Variant 17-78175114-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_003258.5(TK1):c.449C>T(p.Thr150Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000267 in 1,613,256 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

TK1
NM_003258.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.75

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
TK1	NM_003258.5 link	c.449C>T	p.Thr150Met	missense_variant	Exon 6 of 7	ENST00000301634.12	NP_003249.3	P04183A0A384MDV9
TK1	NM_001363848.1 link	c.449C>T	p.Thr150Met	missense_variant	Exon 6 of 6		NP_001350777.1
TK1	NM_001346663.2 link	c.449C>T	p.Thr150Met	missense_variant	Exon 6 of 7		NP_001333592.1	K7ES52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TK1	ENST00000301634.12 link	c.449C>T	p.Thr150Met	missense_variant	Exon 6 of 7	1	NM_003258.5	ENSP00000301634.6		P04183

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000440

AC:

AN:

249990

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135384

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000444

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1461254

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

726908

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000327

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152002

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.449C>T (p.T150M) alteration is located in exon 6 (coding exon 6) of the TK1 gene. This alteration results from a C to T substitution at nucleotide position 449, causing the threonine (T) at amino acid position 150 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;.;.;T

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.52

D;D;D;D

MetaSVM

Uncertain

0.12

MutationAssessor

Uncertain

2.5

M;.;.;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.8

D;.;.;.

REVEL

Uncertain

0.29

Sift

Uncertain

0.0040

D;.;.;.

Sift4G

Uncertain

0.0070

D;D;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.41

MutPred

0.49

Gain of catalytic residue at V146 (P = 0.0324);Gain of catalytic residue at V146 (P = 0.0324);Gain of catalytic residue at V146 (P = 0.0324);.;

MVP

0.68

MPC

1.0

ClinPred

0.64

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.26

gMVP

0.58

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over