chr19-6502208-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP2PP3PP5_Very_Strong
The NM_006087.4(TUBB4A):c.5G>A(p.Arg2Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000709 in 1,410,414 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
Consequence
NM_006087.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 7.09e-7 AC: 1AN: 1410414Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1AN XY: 700424
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypomyelinating leukodystrophy 6 Pathogenic:4Other:1
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The TUBB4A c.5G>A (p.Arg2Gln) missense variant (also known as c.158G>A; p.Arg53Gln) has been reported in two studies in which it is identified in a heterozygous state in two individuals (Hamilton et al. 2014; Miyatake et al. 2014). Hamilton et al. (2014) identified the p.Arg2Gln variant in a presumed de novo state in a non-ambulatory 18 year-old female with nystagmus, intellectual disability, absent speech, g-tube dependent feeding, and abnormal MRI findings including an initially normal putamen and an almost complete lack of myelin. Miyatake et al. (2014) identified the p.Arg2Gln variant in a heterozygous state in a 15-year-old girl with severe intellectual disability, no head control, spasticity, rigidity, choreoathetosis, dystonia and MRI findings consistent with hypomyelinating leukodystrophy. Parental samples were not available for testing. Two additional patients with hypomyelination with atrophy of the basal ganglia and cerebellum with different missense variants at the same residue are also reported (Hamilton et al. 2014). The p.Arg2Gln variant was absent from 575 controls subjects (Miyatake et al. 2014) and is not found in the Genome Aggregation Database in a region of good sequence coverage. The p.Arg2Gln variant occurs within the MREI motif which is involved in autoregulatory mechanisms for beta-tubulin stability (Hersheson et al. 2013). Based on the available evidence and the application of the ACMG criteria, the p.Arg2Gln variant is classified as pathogenic for TUBB4A-related leukodystrophy. -
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Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg2 amino acid residue in TUBB4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23595291). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TUBB4A protein function (PMID: 3405308). ClinVar contains an entry for this variant (Variation ID: 139452). This variant has been observed in individual(s) with clinical features of hypomyelinating leukodystrophy (PMID: 24785942, 24850488). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 2 of the TUBB4A protein (p.Arg2Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -
not provided Pathogenic:1
The R2Q pathogenic variant in the TUBB4A gene has been reported multiple times previously in assocation with atrophy of the basal ganglia and cerebellum (H-ABC) (Miyatake et al., 2014; Hamilton et al., 2014). Additionally, missense variants in the same residue but involving different amino acid substitutions (R2W and R2G) have been reported in association with H-ABC and dystonia type 4 respectively (Hamilton et al., 2014; Hersheson et al., 2013). The R2Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R2Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a highly conserved position within the beta-tubulin tetrapeptide Met-Arg-Glu-Ile (MREI) motif which is involved in autoregulatory mechanisms for beta-tubulin stability (Miyatake et al., 2014). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at