12-49185101-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_006009.4(TUBA1A):c.1265G>A(p.Arg422His) variant causes a missense change. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R422C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

TUBA1A
NM_006009.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 5.82

Variant links:

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]

TUBA1A links:

TUBA1B-AS1 (HGNC:56356): (TUBA1B antisense RNA 1)

TUBA1B-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a helix (size 17) in uniprot entity TBA1A_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) 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 chr12-49185102-G-A is described in Lovd as [Pathogenic].

PP2

Missense variant in the TUBA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 163 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. Gene score misZ: 5.584 (above the threshold of 3.09). Trascript score misZ: 8.7455 (above the threshold of 3.09). GenCC associations: The gene is linked to tubulinopathy-associated dysgyria, intellectual disability, autosomal dominant 40, tubulinopathy, lissencephaly due to TUBA1A mutation.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

PP5

Variant 12-49185101-C-T is Pathogenic according to our data. Variant chr12-49185101-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49185101-C-T is described in Lovd as [Pathogenic]. Variant chr12-49185101-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA1A	NM_006009.4 link	c.1265G>A	p.Arg422His	missense_variant	Exon 4 of 4	ENST00000301071.12	NP_006000.2	Q71U36-1
TUBA1A	NM_001270399.2 link	c.1265G>A	p.Arg422His	missense_variant	Exon 4 of 4		NP_001257328.1	Q71U36-1
TUBA1A	NM_001270400.2 link	c.1160G>A	p.Arg387His	missense_variant	Exon 4 of 4		NP_001257329.1	Q71U36-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12 link	c.1265G>A	p.Arg422His	missense_variant	Exon 4 of 4	1	NM_006009.4	ENSP00000301071.7		Q71U36-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lissencephaly due to TUBA1A mutation

Pathogenic:5Other:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Classic lissencephaly -

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Analysis of the exome sequencing data showed a heterozygous sequence variant in TUBA1A gene. This variant is predicted as Disease Causing by MutationTaster. Sanger sequencing confirmed the variation in the proband. Parents were homozygous for the wildtype allele. -

Nov 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 422 of the TUBA1A protein (p.Arg422His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cortical malformations (PMID: 18728072, 20466733, 26350204, 29671837). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7077). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TUBA1A protein function with a positive predictive value of 80%. This variant disrupts the p.Arg422 amino acid residue in TUBA1A. Other variant(s) that disrupt this residue have been observed in individuals with TUBA1A-related conditions (PMID: 18728072), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Oct 23, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21875651, 25059107, 24860126, 22264709, 18669490, 29671837, 20466733, 26350204, 18954413, 20376468, 22948023, 18728072, 33453472, 30744660) -

Lissencephaly

Pathogenic:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Tubulinopathy

Pathogenic:1

Jul 01, 2018

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

A variant that is classified as pathogenic has been identified in the TUBA1A gene in a 9 years old born individual of male sex. The c.1265G>A, p.(Arg422His) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Morris-Rosendahl et al. Clin Genet, 2008 PMID: 18954413. HPO-standardized clinical features were: Partial agenesis of the corpus callosum (HP:0001338); Pachygyria (HP:0001302); Cerebellar vermis hypoplasia (HP:0001320); Hypoplasia of the pons (HP:0012110); Dysgenesis of the hippocampus (HP:0025101); Dilation of lateral ventricles, Dilated fourth ventricle (HP:0006956, HP:0002198); Gray matter heterotopia (HP:0002281); Congenital microcephaly (HP:0011451); Microcephaly (HP:0000252); Muscular hypotonia (HP:0001252); Generalized tonic-clonic seizures (HP:0002069) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Uncertain

0.54

D;D;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

.;D;D

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Pathogenic

3.9

H;H;.

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.030

D;D;D

Polyphen

0.22

B;B;.

Vest4

0.83

MutPred

0.86

Gain of catalytic residue at R422 (P = 0.1599);Gain of catalytic residue at R422 (P = 0.1599);.;

MVP

0.97

MPC

4.2

ClinPred

1.0

GERP RS

4.6

Varity_R

0.78

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over