17-47696727-A-T

Variant names:

• chr17-47696727-A-T
• rs985502235
• NM_001394755.1:c.242A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001394755.1(TBKBP1):​c.242A>T​(p.Asp81Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TBKBP1 NM_001394755.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.62

Genes affected

TBKBP1 (HGNC:30140): (TBK1 binding protein 1) TBKBP1 is an adaptor protein that binds to TBK1 (MIM 604834) and is part of the interaction network in the TNF (MIM 191160)/NFKB (see MIM 164011) pathway (Bouwmeester et al., 2004 [PubMed 14743216]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBKBP1	NM_001394755.1	c.242A>T	p.Asp81Val	missense_variant	Exon 3 of 10	ENST00000578982.6	NP_001381684.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBKBP1	ENST00000578982.6	c.242A>T	p.Asp81Val	missense_variant	Exon 3 of 10	3	NM_001394755.1	ENSP00000462339.2
TBKBP1	ENST00000361722.7	c.242A>T	p.Asp81Val	missense_variant	Exon 2 of 9	1		ENSP00000354777.3
TBKBP1	ENST00000537587.6	c.242A>T	p.Asp81Val	missense_variant	Exon 3 of 5	3		ENSP00000446365.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.242A>T (p.D81V) alteration is located in exon 2 (coding exon 2) of the TBKBP1 gene. This alteration results from a A to T substitution at nucleotide position 242, causing the aspartic acid (D) at amino acid position 81 to be replaced by a valine (V). 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	Uncertain	0.37
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Benign	0.92
DEOGEN2	Benign	0.070	T;.;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	.;.;L;L
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.5	.;D;D;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.015	.;D;D;.
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		0.79	.;.;P;.
Vest4		0.71, 0.48
MutPred		0.41		Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);
MVP		0.30
MPC		1.3
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.40
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs985502235; hg19: chr17-45774093;