chr8-9556063-G-C

Position:

chr8-9556063-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003747.3(TNKS):c.124G>C(p.Gly42Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000945 in 1,608,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000093 ( 0 hom. )

Consequence

TNKS
NM_003747.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.06

Variant links:

Genes affected

TNKS (HGNC:11941): (tankyrase) Enables histone binding activity; pentosyltransferase activity; and zinc ion binding activity. Involved in several processes, including negative regulation of maintenance of mitotic sister chromatid cohesion, telomeric; protein ADP-ribosylation; and regulation of nucleobase-containing compound metabolic process. Acts upstream of or within peptidyl-serine phosphorylation; peptidyl-threonine phosphorylation; and protein ADP-ribosylation. Located in several cellular components, including chromosome, telomeric region; mitotic spindle pole; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TNKS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07780698).

BS2

High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TNKS	NM_003747.3 linkuse as main transcript	c.124G>C	p.Gly42Arg	missense_variant	1/27	ENST00000310430.11	NP_003738.2
TNKS	XM_011543845.4 linkuse as main transcript	c.124G>C	p.Gly42Arg	missense_variant	1/28		XP_011542147.1
TNKS	XM_011543846.4 linkuse as main transcript	c.124G>C	p.Gly42Arg	missense_variant	1/27		XP_011542148.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNKS	ENST00000310430.11 linkuse as main transcript	c.124G>C	p.Gly42Arg	missense_variant	1/27	1	NM_003747.3	ENSP00000311579	P1	O95271-1
TNKS	ENST00000517770.2 linkuse as main transcript	c.124G>C	p.Gly42Arg	missense_variant	1/28	4		ENSP00000428185
TNKS	ENST00000520408.5 linkuse as main transcript	c.124G>C	p.Gly42Arg	missense_variant	1/11	2		ENSP00000428299
TNKS	ENST00000522110.1 linkuse as main transcript	c.124G>C	p.Gly42Arg	missense_variant	1/1			ENSP00000430920

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000137

AC:

AN:

233594

Hom.:

AF XY:

0.000124

AC XY:

AN XY:

128526

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000148

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000564

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000869

Gnomad OTH exome

AF:

0.000174

GnomAD4 exome

AF:

0.0000934

AC:

136

AN:

1456228

Hom.:

Cov.:

AF XY:

0.000104

AC XY:

AN XY:

724268

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000180

Gnomad4 ASJ exome

AF:

0.0000387

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.000640

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.000105

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000679

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.000117

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.124G>C (p.G42R) alteration is located in exon 1 (coding exon 1) of the TNKS gene. This alteration results from a G to C substitution at nucleotide position 124, causing the glycine (G) at amino acid position 42 to be replaced by an arginine (R). 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

0.21

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

.;T;.

Eigen

Benign

-0.061

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.83

T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.078

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

.;N;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.31

N;N;N

REVEL

Benign

0.064

Sift

Benign

0.051

T;T;D

Sift4G

Benign

0.070

T;T;T

Polyphen

0.077

B;B;.

Vest4

0.47

MutPred

0.25

Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);

MVP

0.30

MPC

0.45

ClinPred

0.11

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.16

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