chr12-64490106-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_ModerateBS1_SupportingBS2_Supporting
The NM_013254.4(TBK1):c.1508C>T(p.Thr503Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,609,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_013254.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBK1 | NM_013254.4 | c.1508C>T | p.Thr503Ile | missense_variant | 13/21 | ENST00000331710.10 | |
TBK1 | XM_005268809.2 | c.1508C>T | p.Thr503Ile | missense_variant | 13/21 | ||
TBK1 | XM_005268810.2 | c.1508C>T | p.Thr503Ile | missense_variant | 13/21 | ||
TBK1 | XR_007063071.1 | n.1607C>T | non_coding_transcript_exon_variant | 13/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBK1 | ENST00000331710.10 | c.1508C>T | p.Thr503Ile | missense_variant | 13/21 | 1 | NM_013254.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152090Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248134Hom.: 0 AF XY: 0.0000224 AC XY: 3AN XY: 134036
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1457882Hom.: 0 Cov.: 29 AF XY: 0.0000303 AC XY: 22AN XY: 725218
GnomAD4 genome AF: 0.0000395 AC: 6AN: 152090Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5AN XY: 74304
ClinVar
Submissions by phenotype
Motor neuron disease Uncertain:1
Uncertain significance, criteria provided, single submitter | case-control | Centre for Genomic and Experimental Medicine, University of Edinburgh | Aug 31, 2016 | - - |
Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 26, 2021 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TBK1 protein function. ClinVar contains an entry for this variant (Variation ID: 266071). This variant has been observed in individual(s) with clinical features of Alzheimer disease or motor neuron disease (PMID: 28089114, 32317127). This variant is present in population databases (rs779715292, ExAC 0.01%). This sequence change replaces threonine with isoleucine at codon 503 of the TBK1 protein (p.Thr503Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at