8-9556366-C-G

Position:

• chr8-9556366-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.427C>G​(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 (★).

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: TNKS NM_003747.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41

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=0.024294466).
• BS2: High AC in GnomAd4 at 96 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNKS	NM_003747.3	c.427C>G	p.Pro143Ala	missense_variant	1/27	ENST00000310430.11	NP_003738.2
TNKS	XM_011543845.4	c.427C>G	p.Pro143Ala	missense_variant	1/28		XP_011542147.1
TNKS	XM_011543846.4	c.427C>G	p.Pro143Ala	missense_variant	1/27		XP_011542148.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNKS	ENST00000310430.11	c.427C>G	p.Pro143Ala	missense_variant	1/27	1	NM_003747.3	ENSP00000311579	P1
TNKS	ENST00000517770.2	c.427C>G	p.Pro143Ala	missense_variant	1/28	4		ENSP00000428185
TNKS	ENST00000520408.5	c.427C>G	p.Pro143Ala	missense_variant	1/11	2		ENSP00000428299
TNKS	ENST00000522110.1	c.427C>G	p.Pro143Ala	missense_variant	1/1			ENSP00000430920

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152228 Hom.: 0 Cov.: 33

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

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

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

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2021

The 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

Other links and lift over

dbSNP: rs147674490; hg19: chr8-9413876;