4-106235347-GT-G

Variant names:

• chr4-106235347-GT-G
• rs746860249
• NM_001163435.3:c.1370delA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001163435.3(TBCK):​c.1370delA​(p.Asn457ThrfsTer15) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,454,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TBCK NM_001163435.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.75
• Publications: 9 publications found

Genes affected

TBCK (HGNC:28261): (TBC1 domain containing kinase) This gene encodes a protein that contains a protein kinase domain, a Rhodanase-like domain and the Tre-2/Bub2/Cdc16 (TBC) domain. The encoded protein is thought to play a role in actin organization, cell growth and cell proliferation by regulating the mammalian target of the rapamycin (mTOR) signaling pathway. This protein may also be involved in the transcriptional regulation of the components of the mTOR complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

TBCK Gene-Disease associations (from GenCC):

• hypotonia, infantile, with psychomotor retardation and characteristic facies 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-106235347-GT-G is Pathogenic according to our data. Variant chr4-106235347-GT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 225241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCK	NM_001163435.3	c.1370delA	p.Asn457ThrfsTer15	frameshift_variant	Exon 15 of 26	ENST00000394708.7	NP_001156907.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCK	ENST00000394708.7	c.1370delA	p.Asn457ThrfsTer15	frameshift_variant	Exon 15 of 26	1	NM_001163435.3	ENSP00000378198.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454874 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723748

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

African (AFR) AF: 0.0000301 AC: 1 AN: 33208

American (AMR) AF: 0.0000226 AC: 1 AN: 44236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25898

East Asian (EAS) AF: 0.00 AC: 0 AN: 39342

South Asian (SAS) AF: 0.00 AC: 0 AN: 85534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108482

Other (OTH) AF: 0.00 AC: 0 AN: 60016

⚠️ 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 Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 Pathogenic:2

Jan 13, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Asn457ThrfsTer15 variant in TBCK has been reported in 2 affected siblings, in the homozygous state, with TBCK-related intellectual disability syndrome (PMID: 27040691), and has been identified in 0.002% (1/59430) of Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs746860249). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. It is of note that this variant occurs in a homopolymer repeat, which could indicate that it is an artifact from sequencing. However, disease-causing variants have been reported in homopolymer regions, so this is not enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 225241) and has been interpreted as pathogenic by OMIM. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 457 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the TBCK gene is an established disease mechanism in autosomal recessive TBCK-related intellectual disability syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive TBCK-related intellectual disability syndrome. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3_supporting (Richards 2015). -

May 19, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Aug 28, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33240423, 35845190, 27040691) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs746860249; hg19: chr4-107156504; COSMIC: COSV56751546; COSMIC: COSV56751546;