12-64455737-A-T

Variant names:

• chr12-64455737-A-T
• rs79531778
• NM_013254.4:c.-31-103A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_013254.4(TBK1):​c.-31-103A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00299 in 630,178 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0089 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (10 hom.)
• Consequence: TBK1 NM_013254.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.266
• Publications: 0 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-64455737-A-T is Benign according to our data. Variant chr12-64455737-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 1199157.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00893 (1361/152332) while in subpopulation AFR AF = 0.0306 (1270/41570). AF 95% confidence interval is 0.0292. There are 19 homozygotes in GnomAd4. There are 681 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBK1	NM_013254.4	c.-31-103A>T		intron_variant	Intron 1 of 20	ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2	c.-31-103A>T		intron_variant	Intron 1 of 20		XP_005268866.1
TBK1	XM_005268810.2	c.-31-103A>T		intron_variant	Intron 1 of 20		XP_005268867.1
TBK1	XR_007063071.1	n.69-103A>T		intron_variant	Intron 1 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10	c.-31-103A>T		intron_variant	Intron 1 of 20	1	NM_013254.4	ENSP00000329967.5

Frequencies

GnomAD3 genomes AF: 0.00893 AC: 1360 AN: 152214 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00110 AC: 525 AN: 477846 Hom.: 10 AF XY: 0.000883 AC XY: 224 AN XY: 253546

African (AFR) AF: 0.0335 AC: 430 AN: 12852

American (AMR) AF: 0.00171 AC: 30 AN: 17558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13854

East Asian (EAS) AF: 0.00 AC: 0 AN: 31680

South Asian (SAS) AF: 0.0000441 AC: 2 AN: 45362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41524

Middle Eastern (MID) AF: 0.000390 AC: 1 AN: 2566

European-Non Finnish (NFE) AF: 0.0000420 AC: 12 AN: 285562

Other (OTH) AF: 0.00186 AC: 50 AN: 26888

GnomAD4 genome AF: 0.00893 AC: 1361 AN: 152332 Hom.: 19 Cov.: 32 AF XY: 0.00914 AC XY: 681 AN XY: 74486

African (AFR) AF: 0.0306 AC: 1270 AN: 41570

American (AMR) AF: 0.00464 AC: 71 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00714 Hom.: 1

Bravo AF: 0.00994

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 18, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.37
DANN	Benign	0.59
PhyloP100		-0.27
PromoterAI		0.0060	Neutral
Mutation Taster		=100/0	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: rs79531778; hg19: chr12-64849517;