rs1143696

chr17-78182670-C-Gchr17-78182670-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003258.5(TK1):c.222G>C(p.Glu74Asp) 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. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TK1 NM_003258.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.337

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21818316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TK1	NM_003258.5	c.222G>C	p.Glu74Asp	missense_variant	4/7	ENST00000301634.12
TK1	NM_001363848.1	c.222G>C	p.Glu74Asp	missense_variant	4/6
TK1	NM_001346663.2	c.222G>C	p.Glu74Asp	missense_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TK1	ENST00000301634.12	c.222G>C	p.Glu74Asp	missense_variant	4/7	1	NM_003258.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	11
Dann	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.;.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.77	T;T;T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.0	N;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.28	T;.;.;.
Sift4G	Benign	0.45	T;T;T;.
Polyphen		0.0	B;.;.;.
Vest4		0.40
MutPred		0.37		Gain of phosphorylation at T72 (P = 0.1969);Gain of phosphorylation at T72 (P = 0.1969);Gain of phosphorylation at T72 (P = 0.1969);.;
MVP		0.29
MPC		0.40
ClinPred		0.32	T
GERP RS		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.56

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

Other links and lift over

dbSNP: rs1143696; hg19: chr17-76178751;