8-9556297-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.358C>Gā€‹(p.Pro120Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,160 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‘“ 0.000039 ( 0 hom., cov: 32)
Exomes š‘“: 0.000018 ( 0 hom. )

Consequence

TNKS
NM_003747.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.985
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=0.061791927).
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TNKSNM_003747.3 linkuse as main transcriptc.358C>G p.Pro120Ala missense_variant 1/27 ENST00000310430.11 NP_003738.2
TNKSXM_011543845.4 linkuse as main transcriptc.358C>G p.Pro120Ala missense_variant 1/28 XP_011542147.1
TNKSXM_011543846.4 linkuse as main transcriptc.358C>G p.Pro120Ala 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.358C>G p.Pro120Ala missense_variant 1/271 NM_003747.3 ENSP00000311579 P1O95271-1
TNKSENST00000517770.2 linkuse as main transcriptc.358C>G p.Pro120Ala missense_variant 1/284 ENSP00000428185
TNKSENST00000520408.5 linkuse as main transcriptc.358C>G p.Pro120Ala missense_variant 1/112 ENSP00000428299
TNKSENST00000522110.1 linkuse as main transcriptc.358C>G p.Pro120Ala missense_variant 1/1 ENSP00000430920

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152268
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251488
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1461892
Hom.:
0
Cov.:
31
AF XY:
0.0000165
AC XY:
12
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152268
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.000955
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000593

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 GeneticsMay 27, 2022The c.358C>G (p.P120A) 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 358, causing the proline (P) at amino acid position 120 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
0.050
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
11
DANN
Benign
0.80
DEOGEN2
Benign
0.28
.;T;.
Eigen
Benign
-0.87
Eigen_PC
Benign
-0.84
FATHMM_MKL
Benign
0.078
N
LIST_S2
Benign
0.77
T;T;T
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.062
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.81
.;L;.
MutationTaster
Benign
0.99
N;N;N
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-0.040
N;N;N
REVEL
Benign
0.18
Sift
Benign
0.73
T;T;D
Sift4G
Benign
0.57
T;T;T
Polyphen
0.0
B;B;.
Vest4
0.23
MutPred
0.18
Loss of catalytic residue at P120 (P = 0.0389);Loss of catalytic residue at P120 (P = 0.0389);Loss of catalytic residue at P120 (P = 0.0389);
MVP
0.36
MPC
0.36
ClinPred
0.055
T
GERP RS
-0.27
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.045
gMVP
0.14

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: rs531198224; hg19: chr8-9413807; API