12-64464320-AT-ATTT

Variant names:

• chr12-64464320-A-ATT
• rs57810028
• NM_013254.4:c.229-5_229-4dupTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_013254.4(TBK1):​c.229-5_229-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,147,622 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 0)
  • Exomes 𝑓: 0.016 (0 hom.)
• Consequence: TBK1 NM_013254.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.04
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• frontotemporal dementia and/or amyotrophic lateral sclerosis 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• frontotemporal dementia with motor neuron disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• autoinflammation with arthritis and vasculitis

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 12-64464320-A-ATT is Benign according to our data. Variant chr12-64464320-A-ATT is described in ClinVar as Benign. ClinVar VariationId is 1981388.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBK1	NM_013254.4	c.229-5_229-4dupTT		splice_region_variant, intron_variant	Intron 3 of 20	ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2	c.229-5_229-4dupTT		splice_region_variant, intron_variant	Intron 3 of 20		XP_005268866.1
TBK1	XM_005268810.2	c.229-5_229-4dupTT		splice_region_variant, intron_variant	Intron 3 of 20		XP_005268867.1
TBK1	XR_007063071.1	n.328-5_328-4dupTT		splice_region_variant, intron_variant	Intron 3 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10	c.229-14_229-13insTT		intron_variant	Intron 3 of 20	1	NM_013254.4	ENSP00000329967.5

Frequencies

GnomAD3 genomes AF: 0.000233 AC: 35 AN: 150498 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000265

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.000691

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000222

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.0136 AC: 2082 AN: 153360 AF XY: 0.0131

Gnomad AFR exome AF: 0.00938

Gnomad AMR exome AF: 0.0246

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.0203

Gnomad FIN exome AF: 0.0138

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.0219

GnomAD4 exome AF: 0.0162 AC: 16166 AN: 997014 Hom.: 0 Cov.: 29 AF XY: 0.0162 AC XY: 8071 AN XY: 497584

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0123 AC: 288 AN: 23500

American (AMR) AF: 0.0225 AC: 510 AN: 22654

Ashkenazi Jewish (ASJ) AF: 0.0200 AC: 323 AN: 16162

East Asian (EAS) AF: 0.0204 AC: 556 AN: 27252

South Asian (SAS) AF: 0.0185 AC: 1061 AN: 57262

European-Finnish (FIN) AF: 0.0200 AC: 666 AN: 33326

Middle Eastern (MID) AF: 0.0111 AC: 42 AN: 3788

European-Non Finnish (NFE) AF: 0.0155 AC: 11986 AN: 772390

Other (OTH) AF: 0.0180 AC: 734 AN: 40680

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000239 AC: 36 AN: 150608 Hom.: 0 Cov.: 0 AF XY: 0.000218 AC XY: 16 AN XY: 73530

African (AFR) AF: 0.0000729 AC: 3 AN: 41134

American (AMR) AF: 0.000265 AC: 4 AN: 15098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5142

South Asian (SAS) AF: 0.000419 AC: 2 AN: 4774

European-Finnish (FIN) AF: 0.000691 AC: 7 AN: 10126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000222 AC: 15 AN: 67592

Other (OTH) AF: 0.00144 AC: 3 AN: 2086

Alfa AF: 0.0375 Hom.: 5204

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 Benign:1

Sep 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs57810028; hg19: chr12-64858100;