12-64464320-AT-ATTTT

Variant names:

• chr12-64464320-A-ATTT
• rs57810028
• NM_013254.4:c.229-6_229-4dupTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_013254.4(TBK1):​c.229-6_229-4dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000567 in 1,058,196 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000057 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBK1 NM_013254.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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: ClinGen, Genomics England PanelApp, 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: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013254.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBK1	NM_013254.4	MANE Select	c.229-6_229-4dupTTT		splice_region intron	N/A	NP_037386.1	Q9UHD2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBK1	ENST00000331710.10	TSL:1 MANE Select	c.229-14_229-13insTTT		intron	N/A	ENSP00000329967.5	Q9UHD2
	TBK1	ENST00000650790.1		c.229-14_229-13insTTT		intron	N/A	ENSP00000498995.1	Q9UHD2
	TBK1	ENST00000911930.1		c.229-14_229-13insTTT		intron	N/A	ENSP00000581989.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 150546 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000117 AC: 18 AN: 153360 AF XY: 0.000108

Gnomad AFR exome AF: 0.0000823

Gnomad AMR exome AF: 0.000258

Gnomad ASJ exome AF: 0.000183

Gnomad EAS exome AF: 0.000269

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000567 AC: 60 AN: 1058196 Hom.: 0 Cov.: 29 AF XY: 0.0000587 AC XY: 31 AN XY: 528148

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

African (AFR) AF: 0.0000408 AC: 1 AN: 24498

American (AMR) AF: 0.000210 AC: 5 AN: 23842

Ashkenazi Jewish (ASJ) AF: 0.000173 AC: 3 AN: 17332

East Asian (EAS) AF: 0.000104 AC: 3 AN: 28844

South Asian (SAS) AF: 0.0000831 AC: 5 AN: 60192

European-Finnish (FIN) AF: 0.0000567 AC: 2 AN: 35256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3960

European-Non Finnish (NFE) AF: 0.0000463 AC: 38 AN: 821120

Other (OTH) AF: 0.0000695 AC: 3 AN: 43152

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 150546 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 73440

African (AFR) AF: 0.00 AC: 0 AN: 41024

American (AMR) AF: 0.00 AC: 0 AN: 15084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67616

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.00139 Hom.: 5204

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0

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;