rs863224938
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP2PP5_Very_Strong
The NM_006009.4(TUBA1A):c.352G>C(p.Val118Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V118M) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
TUBA1A
NM_006009.4 missense
NM_006009.4 missense
Scores
5
8
5
Clinical Significance
Conservation
PhyloP100: 7.56
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 15 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006009.4
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr12-49186333-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
?
Missense variant where missense usually causes diseases, TUBA1A
PP5
?
Variant 12-49186333-C-G is Pathogenic according to our data. Variant chr12-49186333-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 625508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49186333-C-G is described in Lovd as [Likely_pathogenic]. Variant chr12-49186333-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TUBA1A | NM_006009.4 | c.352G>C | p.Val118Leu | missense_variant | 3/4 | ENST00000301071.12 | |
TUBA1A | NM_001270399.2 | c.352G>C | p.Val118Leu | missense_variant | 3/4 | ||
TUBA1A | NM_001270400.2 | c.247G>C | p.Val83Leu | missense_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TUBA1A | ENST00000301071.12 | c.352G>C | p.Val118Leu | missense_variant | 3/4 | 1 | NM_006009.4 | P1 | |
TUBA1B-AS1 | ENST00000656133.1 | n.474-1950C>G | intron_variant, non_coding_transcript_variant |
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: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
TUBA1A-associated tubulinopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has been previously reported as a de novo change in a 3 years-old boy with delayed development, spastic tetraparesis, severe ID, congenital microcephaly and focal seizures (PMID: 28677066). A different missense variant affecting the same amino acid residue (c.352G>A, p.Val118Met) has been previously reported in a 4 year-old individual with astigmatism, early tooth eruption, premature adult teeth, brain malformation, developmental delay, spasticity, hyperreflexia and wide based gait (PMID: 25326637). The TUBA1A gene is constrained against variation (Z-score= 5.58 and pLI = 0.97), and missense variants have been reported in individuals with TUBA1A-associated tubulinopathy (HGMD, ClinVar database; PMID: 24860126, 28677066, 25326637). The c.352G>C variant is absent from the gnomAD population database and thus is presumed to be rare. The c.352G>C variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.352G>C variant is classified as Pathogenic. - |
Tubulinopathy Pathogenic:1
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 pathogenic has been identified in the TUBA1A gene in a 30 months old born individual of male sex. The c.352G>C, p.(Val118Leu) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Romaniello et al. Eur Radiol, 2017 PMID: 28677066. HPO-standardized clinical features were: Agenesis of the corpus callosum (HP:0001274); Cortical gyral simplification (HP:0009879); Dysgenesis of the cerebellar vermis (HP:0002195); Brainstem dysplasia (HP:0002508); Dilated fourth ventricle (HP:0002198); Abnormality of the internal capsule (HP:0012502); Congenital microcephaly (HP:0011451); Spasticity (HP:0001257); Focal seizures (HP:0007359) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N;N;D
REVEL
Uncertain
Sift
Uncertain
D;D;.;.;.
Sift4G
Uncertain
D;D;D;.;T
Polyphen
B;B;.;.;.
Vest4
MutPred
Gain of catalytic residue at L119 (P = 0.0085);Gain of catalytic residue at L119 (P = 0.0085);.;.;.;
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