rs780472451
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_003193.5(TBCE):c.464T>A(p.Ile155Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000412 in 1,455,882 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
TBCE
NM_003193.5 missense
NM_003193.5 missense
Scores
3
6
3
Clinical Significance
Conservation
PhyloP100: 4.79
Genes affected
TBCE (HGNC:11582): (tubulin folding cofactor E) Cofactor E 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. Two transcript variants encoding the same protein have been found for this gene. [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, 0.914
PP5
?
Variant 1-235427143-T-A is Pathogenic according to our data. Variant chr1-235427143-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-235427143-T-A is described in UniProt as null. Variant chr1-235427143-T-A is described in UniProt as null. Variant chr1-235427143-T-A is described in UniProt as null. Variant chr1-235427143-T-A is described in UniProt as null. Variant chr1-235427143-T-A is described in UniProt as null. Variant chr1-235427143-T-A is described in UniProt as null. Variant chr1-235427143-T-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TBCE | NM_003193.5 | c.464T>A | p.Ile155Asn | missense_variant | 6/17 | ENST00000642610.2 | |
TBCE | NM_001287801.2 | c.464T>A | p.Ile155Asn | missense_variant | 6/18 | ||
TBCE | NM_001079515.3 | c.464T>A | p.Ile155Asn | missense_variant | 6/17 | ||
TBCE | NM_001287802.2 | c.125T>A | p.Ile42Asn | missense_variant | 5/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TBCE | ENST00000642610.2 | c.464T>A | p.Ile155Asn | missense_variant | 6/17 | NM_003193.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000412 AC: 6AN: 1455882Hom.: 0 Cov.: 29 AF XY: 0.00000414 AC XY: 3AN XY: 724692
GnomAD4 exome
AF:
AC:
6
AN:
1455882
Hom.:
Cov.:
29
AF XY:
AC XY:
3
AN XY:
724692
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
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ExAC
?
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AC:
1
EpiCase
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EpiControl
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 12, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 155 of the TBCE protein (p.Ile155Asn). This variant is present in population databases (rs780472451, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of progressive encephalopathy with amyotrophy and optic atrophy (PMID: 27666369). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 372201). 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 TBCE protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 17, 2021 | Not observed at a significant frequency in GeneDX; 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: 27666369) - |
Encephalopathy, progressive, with amyotrophy and optic atrophy Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 29, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Polyphen
1.0
.;D;D;D;D;D;.;D;D;D;.;.;.;.;.;.
Vest4
0.88, 0.84
MutPred
0.82
.;Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);.;.;.;Gain of disorder (P = 0.0124);Gain of disorder (P = 0.0124);
MVP
0.75
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at