chr8-9556366-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003747.3(TNKS):ā€‹c.427C>Gā€‹(p.Pro143Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000672 in 1,614,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00063 ( 0 hom., cov: 33)
Exomes š‘“: 0.00068 ( 0 hom. )

Consequence

TNKS
NM_003747.3 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.41
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.024294466).
BS2
High AC in GnomAd4 at 96 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TNKSNM_003747.3 linkuse as main transcriptc.427C>G p.Pro143Ala missense_variant 1/27 ENST00000310430.11 NP_003738.2
TNKSXM_011543845.4 linkuse as main transcriptc.427C>G p.Pro143Ala missense_variant 1/28 XP_011542147.1
TNKSXM_011543846.4 linkuse as main transcriptc.427C>G p.Pro143Ala missense_variant 1/27 XP_011542148.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TNKSENST00000310430.11 linkuse as main transcriptc.427C>G p.Pro143Ala missense_variant 1/271 NM_003747.3 ENSP00000311579 P1O95271-1
TNKSENST00000517770.2 linkuse as main transcriptc.427C>G p.Pro143Ala missense_variant 1/284 ENSP00000428185
TNKSENST00000520408.5 linkuse as main transcriptc.427C>G p.Pro143Ala missense_variant 1/112 ENSP00000428299
TNKSENST00000522110.1 linkuse as main transcriptc.427C>G p.Pro143Ala missense_variant 1/1 ENSP00000430920

Frequencies

GnomAD3 genomes
AF:
0.000631
AC:
96
AN:
152228
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000265
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000785
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000985
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.000549
AC:
138
AN:
251490
Hom.:
0
AF XY:
0.000522
AC XY:
71
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.000694
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000231
Gnomad NFE exome
AF:
0.000879
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000677
AC:
989
AN:
1461880
Hom.:
0
Cov.:
31
AF XY:
0.000710
AC XY:
516
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.000760
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.000131
Gnomad4 NFE exome
AF:
0.000815
Gnomad4 OTH exome
AF:
0.000546
GnomAD4 genome
AF:
0.000630
AC:
96
AN:
152346
Hom.:
0
Cov.:
33
AF XY:
0.000564
AC XY:
42
AN XY:
74510
show subpopulations
Gnomad4 AFR
AF:
0.000265
Gnomad4 AMR
AF:
0.000784
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000985
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.000629
Hom.:
0
Bravo
AF:
0.000616
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00105
AC:
9
ExAC
AF:
0.000610
AC:
74
EpiCase
AF:
0.00109
EpiControl
AF:
0.00142

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 submitterclinical testingAmbry GeneticsOct 19, 2021The c.427C>G (p.P143A) alteration is located in exon 1 (coding exon 1) of the TNKS gene. This alteration results from a C to G substitution at nucleotide position 427, causing the proline (P) at amino acid position 143 to be replaced by an alanine (A). 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
0.059
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.27
.;T;.
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.11
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.79
T;T;T
M_CAP
Benign
0.029
D
MetaRNN
Benign
0.024
T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.0
.;N;.
MutationTaster
Benign
0.88
N;N;N
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
0.18
N;N;N
REVEL
Benign
0.12
Sift
Uncertain
0.018
D;D;D
Sift4G
Benign
0.37
T;T;T
Polyphen
0.24
B;B;.
Vest4
0.33
MVP
0.37
MPC
0.36
ClinPred
0.034
T
GERP RS
3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.078
gMVP
0.18

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.

Other links and lift over

dbSNP: rs147674490; hg19: chr8-9413876; API