chr8-9556006-G-A

Variant names:

• chr8-9556006-G-A
• rs1248874882
• NM_003747.3:c.67G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003747.3(TNKS):​c.67G>A​(p.Gly23Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNKS NM_003747.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.74
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26995632).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNKS	NM_003747.3	c.67G>A	p.Gly23Arg	missense_variant	Exon 1 of 27	ENST00000310430.11	NP_003738.2
TNKS	XM_011543845.4	c.67G>A	p.Gly23Arg	missense_variant	Exon 1 of 28		XP_011542147.1
TNKS	XM_011543846.4	c.67G>A	p.Gly23Arg	missense_variant	Exon 1 of 27		XP_011542148.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNKS	ENST00000310430.11	c.67G>A	p.Gly23Arg	missense_variant	Exon 1 of 27	1	NM_003747.3	ENSP00000311579.6
TNKS	ENST00000517770.2	c.67G>A	p.Gly23Arg	missense_variant	Exon 1 of 28	4		ENSP00000428185.2
TNKS	ENST00000520408.5	c.67G>A	p.Gly23Arg	missense_variant	Exon 1 of 11	2		ENSP00000428299.1
TNKS	ENST00000522110.1	c.67G>A	p.Gly23Arg	missense_variant	Exon 1 of 1	6		ENSP00000430920.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460820 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726712

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111820

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	D;T;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.0	.;N;.
PhyloP100		4.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.29	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.035	D;T;D
Sift4G	Benign	0.16	T;T;D
Polyphen		0.98	D;B;.
Vest4		0.47
MutPred		0.24		Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);
MVP		0.44
MPC		0.45
ClinPred		0.82	D
GERP RS		4.7
PromoterAI		0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.081
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs1248874882; hg19: chr8-9413516; COSMIC: COSV60058829;