rs587784491
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_001270400.2(TUBA1A):c.-101G>A variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 31)
Consequence
TUBA1A
NM_001270400.2 5_prime_UTR_premature_start_codon_gain
NM_001270400.2 5_prime_UTR_premature_start_codon_gain
Scores
7
8
4
Splicing: ADA: 0.9802
2
Clinical Significance
Conservation
PhyloP100: 6.09
Genes affected
TUBA1A (HGNC:20766): (tubulin alpha 1a) Microtubules of the eukaryotic cytoskeleton perform essential and diverse functions and are composed of a heterodimer of alpha and beta tubulins. The genes encoding these microtubule constituents belong to the tubulin superfamily, which is composed of six distinct families. Genes from the alpha, beta and gamma tubulin families are found in all eukaryotes. The alpha and beta tubulins represent the major components of microtubules, while gamma tubulin plays a critical role in the nucleation of microtubule assembly. There are multiple alpha and beta tubulin genes, which are highly conserved among species. This gene encodes alpha tubulin and is highly similar to the mouse and rat Tuba1 genes. Northern blot studies have shown that the gene expression is predominantly found in morphologically differentiated neurologic cells. This gene is one of three alpha-tubulin genes in a cluster on chromosome 12q. Mutations in this gene cause lissencephaly type 3 (LIS3) - a neurological condition characterized by microcephaly, intellectual disability, and early-onset epilepsy caused by defective neuronal migration. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-49186832-C-T is Pathogenic according to our data. Variant chr12-49186832-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 160161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49186832-C-T is described in Lovd as [Pathogenic]. Variant chr12-49186832-C-T is described in Lovd as [Likely_pathogenic]. Variant chr12-49186832-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TUBA1A | NM_006009.4 | c.5G>A | p.Arg2His | missense_variant, splice_region_variant | 2/4 | ENST00000301071.12 | NP_006000.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TUBA1A | ENST00000301071.12 | c.5G>A | p.Arg2His | missense_variant, splice_region_variant | 2/4 | 1 | NM_006009.4 | ENSP00000301071.7 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 39
GnomAD4 exome
Cov.:
39
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Lissencephaly due to TUBA1A mutation Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with lissencephaly 3, resulting in defects in protein stability (MIM#61160; PMIDs: 20466733, 30517687). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative change to serine at the same residue has been reported as pathogenic (ClinVar). (SP). 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a recurrent pathogenic variant in patients with shared features including developmental delay, microcephaly, hypoplasia and thinning of the corpus callosum (ClinVar; LOVD; PMID: 30087272). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional and computer modelling suggest that p.(Arg2His) has subtle effects on microtubule function, possibly acting at the interdimer interface (PMID: 30087272). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 09, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 26, 2019 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 15, 2023 | The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30744660, 34490615, 30087272, 25131622, 25356970, 31696992, 32581362, 34402213, 33604570, 24077912, 35017693) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 23, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2 of the TUBA1A protein (p.Arg2His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tubulinopathy (PMID: 30087272). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 160161). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TUBA1A function (PMID: 30087272). For these reasons, this variant has been classified as Pathogenic. - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 16, 2013 | ​The c.5G>A (p.R2H) alteration is located in exon 2 of the TUBA1A gene. This alteration results from a G to A substitution at nucleotide position 5. The arginine (R) at codon 2 is replaced by histidine (H).The missense change is not observed in healthy cohorts:Based on data from the NHLBI Exome Sequencing Project (ESP), the TUBA1A c.5G>A (p.R2H) alteration was not observed among 6,503 individuals tested (0.0%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP).The altered amino acid is conserved throughout evolution:The p.R2 amino acid is conserved throughout vertebrates.in silico prediction is conflicting:The p.R2H alteration is predicted to be benign by PolyPhen but deleterious by SIFT in silico analyses.Co-segregation analysis in our laboratory of the c.5G>A (p.R2H) alteration revealed that the unaffected mother and father did not carry this alteration, indicating a likely de novo mutation occurrence. (Note that the possibility for germline mosaicism cannot be ruled out.)Based on the available evidence, the c.5G>A (p.R2H) alteration is classified as a pathogenic mutation. - |
Neurodevelopmental disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Oct 27, 2020 | - - |
TUBA1A-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 02, 2024 | The TUBA1A c.5G>A variant is predicted to result in the amino acid substitution p.Arg2His. This variant has been reported as a reoccurring de novo variant in multiple individuals with lissencephaly (see for example, Table 1, Gardner et al. 2018. PubMed ID: 30087272; Table 1, Stutterd et al. 2020. PubMed ID: 33604570; Table 1, Schröter et al. 2022. PubMed ID: 35017693). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. - |
Seizure;C0424688:Decreased head circumference;C0557874:Global developmental delay Pathogenic:1
| Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Tubulinopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | literature only | Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg | Jul 01, 2018 | A variant that is classified as likely pathogenic has been identified in the TUBA1A gene in a born individual of unknown sex. The c.5G>A, p.(Arg2His) variant has been reported as a variant of germline/unknown origin. - |
Tubulinopathy-associated dysgyria Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg | Nov 01, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;D;T
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M;M;.
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;D
REVEL
Uncertain
Sift
Uncertain
D;D;T
Sift4G
Benign
T;T;T
Polyphen
P;P;.
Vest4
MutPred
Gain of catalytic residue at S6 (P = 9e-04);Gain of catalytic residue at S6 (P = 9e-04);Gain of catalytic residue at S6 (P = 9e-04);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at