NM_003258.5:c.596G>T

Variant names:

• chr17-78174868-C-A
• rs386352371
• NM_003258.5:c.596G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003258.5(TK1):​c.596G>T​(p.Gly199Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G199R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TK1 NM_003258.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.160
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08543274).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003258.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TK1	NM_003258.5	MANE Select	c.596G>T	p.Gly199Val	missense	Exon 7 of 7	NP_003249.3	A0A384MDV9
	TK1	NM_001363848.1		c.695G>T	p.Gly232Val	missense	Exon 6 of 6	NP_001350777.1	K7ERV3
	TK1	NM_001346663.2		c.514-80G>T		intron	N/A	NP_001333592.1	K7ES52

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TK1	ENST00000301634.12	TSL:1 MANE Select	c.596G>T	p.Gly199Val	missense	Exon 7 of 7	ENSP00000301634.6	P04183
	TK1	ENST00000588734.6	TSL:2	c.695G>T	p.Gly232Val	missense	Exon 6 of 6	ENSP00000468425.1	K7ERV3
	TK1	ENST00000944215.1		c.674G>T	p.Gly225Val	missense	Exon 6 of 6	ENSP00000614274.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.2
DANN	Benign	0.97
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.16
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.033
Sift	Benign	0.15	T
Sift4G	Benign	0.087	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.22		Gain of ubiquitination at K203 (P = 0.0745)
MVP		0.20
MPC		0.57
ClinPred		0.13	T
GERP RS		-0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.042
gMVP		0.28

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: rs386352371; hg19: chr17-76170949;