8-9555997-C-G

Position:

• chr8-9555997-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003747.3(TNKS):​c.58C>G​(p.Pro20Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,461,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TNKS NM_003747.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.559

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.109665036).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNKS	NM_003747.3	c.58C>G	p.Pro20Ala	missense_variant	1/27	ENST00000310430.11	NP_003738.2
TNKS	XM_011543845.4	c.58C>G	p.Pro20Ala	missense_variant	1/28		XP_011542147.1
TNKS	XM_011543846.4	c.58C>G	p.Pro20Ala	missense_variant	1/27		XP_011542148.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNKS	ENST00000310430.11	c.58C>G	p.Pro20Ala	missense_variant	1/27	1	NM_003747.3	ENSP00000311579	P1
TNKS	ENST00000517770.2	c.58C>G	p.Pro20Ala	missense_variant	1/28	4		ENSP00000428185
TNKS	ENST00000520408.5	c.58C>G	p.Pro20Ala	missense_variant	1/11	2		ENSP00000428299
TNKS	ENST00000522110.1	c.58C>G	p.Pro20Ala	missense_variant	1/1			ENSP00000430920

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1461058 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726828

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Apr 13, 2022

The c.58C>G (p.P20A) 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 58, causing the proline (P) at amino acid position 20 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	0.049
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.27	.;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.010	N;N;N
REVEL	Benign	0.029
Sift	Benign	0.27	T;T;D
Sift4G	Benign	0.55	T;T;T
Polyphen		0.037	B;B;.
Vest4		0.33
MutPred		0.20		Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);
MVP		0.35
MPC		0.36
ClinPred		0.32	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.073

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: rs1815266339; hg19: chr8-9413507;