rs775014444
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_005993.5(TBCD):c.1423G>A(p.Ala475Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
TBCD
NM_005993.5 missense
NM_005993.5 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 7.26
Genes affected
TBCD (HGNC:11581): (tubulin folding cofactor D) Cofactor D is one of four proteins (cofactors A, D, E, and C) involved in the pathway leading to correctly folded beta-tubulin from folding intermediates. Cofactors A and D are believed to play a role in capturing and stabilizing beta-tubulin intermediates in a quasi-native confirmation. Cofactor E binds to the cofactor D/beta-tubulin complex; interaction with cofactor C then causes the release of beta-tubulin polypeptides that are committed to the native state. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.897
PP5
?
Variant 17-82870328-G-A is Pathogenic according to our data. Variant chr17-82870328-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 279953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-82870328-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBCD | NM_005993.5 | c.1423G>A | p.Ala475Thr | missense_variant | 14/39 | ENST00000355528.9 | |
LOC124904096 | XR_007065971.1 | n.2299C>T | non_coding_transcript_exon_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBCD | ENST00000355528.9 | c.1423G>A | p.Ala475Thr | missense_variant | 14/39 | 1 | NM_005993.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248244Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134938
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461130Hom.: 0 Cov.: 37 AF XY: 0.00000825 AC XY: 6AN XY: 726860
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Mar 01, 2023 | The missense variant c.1423G>A(p.Ala475Thr) in TBCD gene has been reported in homozygous state in individuals with early-onset encephalopathy with brain atrophy and thin corpus callosum (Stephen J, et al., 2018). Experimental studes have shown that this missense change alters TBCD gene expression (Pode-Shakked B,et al., 2017). The variant has 0.001% allele frequency in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Alanine at position 475 is changed to a Threonine changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic. The variant is predicted to be damaging by SIFT. The amino acid change p.Ala475Thr in TBCD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Suma Genomics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 15, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 19, 2024 | Variant summary: TBCD c.1423G>A (p.Ala475Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248244 control chromosomes (gnomAD). c.1423G>A has been reported in the literature in multiple individuals affected with infantile neurodegenerative disorders including Encephalopathy, Early Onset (e.g. Edvardson_2016, AlAbdi_2023). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding ~10% of normal TBCD intracellular abundance in fibroblasts from homozygous patient fibroblasts (Edvardson_2016). The following publications have been ascertained in the context of this evaluation (PMID: 28158450, 37644014). ClinVar contains an entry for this variant (Variation ID: 279953). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 19, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 475 of the TBCD protein (p.Ala475Thr). This variant is present in population databases (rs775014444, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of progressive early-onset encephalopathy with brain atrophy and thin corpus callosum (PMID: 27807845, 28158450, 29769041). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 279953). 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 expected to disrupt TBCD protein function. Studies have shown that this missense change alters TBCD gene expression (PMID: 27807845). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 26, 2023 | Published functional studies demonstrate a damaging effect with reduction of protein expression in patient fibroblasts (Edvardson S et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31625567, 27807845, 29769041, 28158450) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Gain of phosphorylation at A475 (P = 0.2524);Gain of phosphorylation at A475 (P = 0.2524);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at