chr19-6495736-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5
The NM_006087.4(TUBB4A):c.763G>A(p.Val255Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
TUBB4A
NM_006087.4 missense
NM_006087.4 missense
Scores
6
7
5
Clinical Significance
Conservation
PhyloP100: 7.69
Genes affected
TUBB4A (HGNC:20774): (tubulin beta 4A class IVa) This gene encodes a member of the beta tubulin family. Beta tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. Mutations in this gene cause hypomyelinating leukodystrophy-6 and autosomal dominant torsion dystonia-4. Alternate splicing results in multiple transcript variants encoding different isoforms. A pseudogene of this gene is found on chromosome X. [provided by RefSeq, Jan 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_006087.4
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, TUBB4A
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.909
PP5
?
Variant 19-6495736-C-T is Pathogenic according to our data. Variant chr19-6495736-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217025.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, not_provided=1, Likely_pathogenic=2, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TUBB4A | NM_006087.4 | c.763G>A | p.Val255Ile | missense_variant | 4/4 | ENST00000264071.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TUBB4A | ENST00000264071.7 | c.763G>A | p.Val255Ile | missense_variant | 4/4 | 1 | NM_006087.4 | P1 | |
TUBB4A | ENST00000594276.5 | c.451G>A | p.Val151Ile | missense_variant | 3/3 | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:8Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hypomyelinating leukodystrophy 6 Pathogenic:3Uncertain:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2023 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 255 of the TUBB4A protein (p.Val255Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dystonia, isolated hypomyelination, or dystonia with hypomyelinating leukodystrophy (PMID: 25085639, 25326637; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 217025). 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 TUBB4A protein function. Experimental studies have shown that this missense change affects TUBB4A function (PMID: 28973395). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | UCLA Clinical Genomics Center, UCLA | Apr 02, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Pathogenic, criteria provided, single submitter | research | TIDEX, University of British Columbia | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 18, 2021 | Published functional studies demonstrate a damaging effect with significant reduction in tubulin polymerization and altered ability to incorporate into microtubules, suggestive of a toxic dominant gain-of-function mechanism (Curiel et al, 2017); Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 26934450, 25326637, 25085639, 27809427, 28973395, 32581362, 30542205) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 17, 2021 | - - |
Microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Bicknell laboratory, University of Otago | - | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 04, 2021 | The c.763G>A (p.V255I) alteration is located in exon 4 (coding exon 4) of the TUBB4A gene. This alteration results from a G to A substitution at nucleotide position 763, causing the valine (V) at amino acid position 255 to be replaced by an isoleucine (I). Based on data from the Genome Aggregation Database (gnomAD), the TUBB4A c.763G>A alteration was not observed, with coverage at this position. This alteration was reported de novo in a 5 year old girl with spastic quadriparesis, hypotonia, ataxia, developmental delay, and a brain MRI showing hypomyelination and mild cerebellar vermis atrophy (Pizzino, 2014). This alteration was reported de novo in another patient with developmental delay, microcephaly, truncal hypotonia, limb hypertonia, foot clonus, and cerebellar hypoplasia/atrophy (Lee, 2014). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Histo-pathological examination of brain tissue from affected individuals with the p.V255I alteration showed abnormal morphology of oligodendrocytes, and in vitro functional studies showed decreased tubulin polymerization and decreased myelin protein expression (Curiel, 2017). The p.V255I alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. - |
Cerebral palsy Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
T
PROVEAN
Benign
N;.
REVEL
Pathogenic
Sift4G
Uncertain
D;D
Polyphen
P;.
Vest4
MutPred
Gain of ubiquitination at K252 (P = 0.0846);.;
MVP
MPC
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