17-78174870-G-A

Position:

• chr17-78174870-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003258.5(TK1):​c.594C>T​(p.Ala198Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 1,613,828 control chromosomes in the GnomAD database, including 283 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (156 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (127 hom.)
• Consequence: TK1 NM_003258.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.61

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 17-78174870-G-A is Benign according to our data. Variant chr17-78174870-G-A is described in ClinVar as [Benign]. Clinvar id is 785585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.61 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TK1	NM_003258.5	c.594C>T	p.Ala198Ala	synonymous_variant	7/7	ENST00000301634.12	NP_003249.3
TK1	NM_001363848.1	c.693C>T	p.Ala231Ala	synonymous_variant	6/6		NP_001350777.1
TK1	NM_001346663.2	c.514-82C>T		intron_variant			NP_001333592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TK1	ENST00000301634.12	c.594C>T	p.Ala198Ala	synonymous_variant	7/7	1	NM_003258.5	ENSP00000301634.6
TK1	ENST00000588734.5	c.693C>T	p.Ala231Ala	synonymous_variant	6/6	2		ENSP00000468425.1
TK1	ENST00000590430.5	c.*335C>T		3_prime_UTR_variant	5/5	3		ENSP00000467121.1
TK1	ENST00000590862.5	c.514-82C>T		intron_variant		3		ENSP00000468556.1

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3453 AN: 152216 Hom.: 156 Cov.: 32

Gnomad AFR AF: 0.0795

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00588 AC: 1457 AN: 247636 Hom.: 67 AF XY: 0.00410 AC XY: 551 AN XY: 134262

Gnomad AFR exome AF: 0.0823

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000543

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.00229 AC: 3344 AN: 1461494 Hom.: 127 Cov.: 33 AF XY: 0.00194 AC XY: 1407 AN XY: 727010

Gnomad4 AFR exome AF: 0.0842

Gnomad4 AMR exome AF: 0.00331

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.00480

GnomAD4 genome AF: 0.0227 AC: 3458 AN: 152334 Hom.: 156 Cov.: 32 AF XY: 0.0222 AC XY: 1656 AN XY: 74494

Gnomad4 AFR AF: 0.0793

Gnomad4 AMR AF: 0.00706

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00849 Hom.: 22

Bravo AF: 0.0256

Asia WGS AF: 0.00491 AC: 18 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.3
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1065767; hg19: chr17-76170951;