chr12-64495773-G-A

Position:

chr12-64495773-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4BS1_SupportingBS2_Supporting

The NM_013254.4(TBK1):c.1718G>A(p.Arg573His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000631 in 1,568,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

TBK1
NM_013254.4 missense, splice_region

Scores

Splicing: ADA: 0.9246

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.78

Variant links:

Genes affected

TBK1 (HGNC:11584): (TANK binding kinase 1) The NF-kappa-B (NFKB) complex of proteins is inhibited by I-kappa-B (IKB) proteins, which inactivate NFKB by trapping it in the cytoplasm. Phosphorylation of serine residues on the IKB proteins by IKB kinases marks them for destruction via the ubiquitination pathway, thereby allowing activation and nuclear translocation of the NFKB complex. The protein encoded by this gene is similar to IKB kinases and can mediate NFKB activation in response to certain growth factors. The protein is also an important kinase for antiviral innate immunity response. [provided by RefSeq, Sep 2021]

TBK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32650632).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000526 (8/152234) while in subpopulation AFR AF= 0.000169 (7/41542). AF 95% confidence interval is 0.0000788. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 8 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TBK1	NM_013254.4 linkuse as main transcript	c.1718G>A	p.Arg573His	missense_variant, splice_region_variant	15/21	ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2 linkuse as main transcript	c.1718G>A	p.Arg573His	missense_variant, splice_region_variant	15/21		XP_005268866.1
TBK1	XM_005268810.2 linkuse as main transcript	c.1718G>A	p.Arg573His	missense_variant, splice_region_variant	15/21		XP_005268867.1
TBK1	XR_007063071.1 linkuse as main transcript	n.1817G>A		splice_region_variant, non_coding_transcript_exon_variant	15/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10 linkuse as main transcript	c.1718G>A	p.Arg573His	missense_variant, splice_region_variant	15/21	1	NM_013254.4	ENSP00000329967	P4

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000363

AC:

AN:

192908

Hom.:

AF XY:

0.0000570

AC XY:

AN XY:

105330

show subpopulations

Gnomad AFR exome

AF:

0.0000776

Gnomad AMR exome

AF:

0.0000903

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000457

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000643

AC:

AN:

1415890

Hom.:

Cov.:

AF XY:

0.0000512

AC XY:

AN XY:

703124

show subpopulations

Gnomad4 AFR exome

AF:

0.0000968

Gnomad4 AMR exome

AF:

0.0000907

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.0000704

Gnomad4 OTH exome

AF:

0.000120

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.000169

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000776

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 02, 2023

This variant disrupts the p.Arg573 amino acid residue in TBK1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28365590). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 475936). This variant has been reported in the amyotrophic lateral sclerosis variant database (PMID: 25700176, www.alsdb.org). This variant is present in population databases (rs186475789, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 573 of the TBK1 protein (p.Arg573His). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.035

MetaRNN

Benign

0.33

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.22

Sift

Benign

0.033

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.46

MVP

0.48

MPC

1.2

ClinPred

0.56

GERP RS

4.8

Varity_R

0.50

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.92

dbscSNV1_RF

Pathogenic

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over