8-9556297-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003747.3(TNKS):c.358C>G(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 (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: TNKS NM_003747.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.985

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.061791927).
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNKS	NM_003747.3	c.358C>G	p.Pro120Ala	missense_variant	1/27	ENST00000310430.11
TNKS	XM_011543845.4	c.358C>G	p.Pro120Ala	missense_variant	1/28
TNKS	XM_011543846.4	c.358C>G	p.Pro120Ala	missense_variant	1/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNKS	ENST00000310430.11	c.358C>G	p.Pro120Ala	missense_variant	1/27	1	NM_003747.3	P1
TNKS	ENST00000517770.2	c.358C>G	p.Pro120Ala	missense_variant	1/28	4
TNKS	ENST00000520408.5	c.358C>G	p.Pro120Ala	missense_variant	1/11	2
TNKS	ENST00000522110.1	c.358C>G	p.Pro120Ala	missense_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152268 Hom.: 0 Cov.: 32

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

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

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

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The 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
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
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

Other links and lift over

dbSNP: rs531198224; hg19: chr8-9413807;