12-49185714-C-T

Variant names:

• chr12-49185714-C-T
• rs1057517858
• NM_006009.4:c.652G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP5

The NM_006009.4(TUBA1A):​c.652G>A​(p.Asp218Asn) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D218Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TUBA1A NM_006009.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 7.25
• Publications: 10 publications found

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]

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 11 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 chr12-49185714-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 625499.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, lissencephaly due to TUBA1A mutation, tubulinopathy-associated dysgyria.
• PP5: Variant 12-49185714-C-T is Pathogenic according to our data. Variant chr12-49185714-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372561.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA1A	NM_006009.4	c.652G>A	p.Asp218Asn	missense_variant	Exon 4 of 4	ENST00000301071.12	NP_006000.2
TUBA1A	NM_001270399.2	c.652G>A	p.Asp218Asn	missense_variant	Exon 4 of 4		NP_001257328.1
TUBA1A	NM_001270400.2	c.547G>A	p.Asp183Asn	missense_variant	Exon 4 of 4		NP_001257329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12	c.652G>A	p.Asp218Asn	missense_variant	Exon 4 of 4	1	NM_006009.4	ENSP00000301071.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 218 of the TUBA1A protein (p.Asp218Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TUBA1A-related conditions (PMID: 31474318, 31628766, 33077954). ClinVar contains an entry for this variant (Variation ID: 372561). 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 not expected to disrupt TUBA1A protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Dec 14, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31628766, 33077954, 31474318) -

Corpus callosum, agenesis of;C4305153:Lissencephaly due to TUBA1A mutation;CN274613:Genetic syndrome with a Dandy-Walker malformation as major feature Pathogenic:1

Feb 18, 2019

Dobyns Lab, Seattle Children's Research Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Inborn genetic diseases Pathogenic:1

Sep 19, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dandy-Walker syndrome Pathogenic:1

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Lissencephaly due to TUBA1A mutation Pathogenic:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TUBA1A-related disorder Pathogenic:1

Mar 07, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TUBA1A c.652G>A variant is predicted to result in the amino acid substitution p.Asp218Asn. This variant has been reported in the de novo state in multiple individuals with TUBA1A related diseases (Aldinger et al. 2019. PubMed ID: 31474318. Table S5; Powis et al. 2019. PubMed ID: 31628766. Supplementary; Jin et al. 2020. PubMed ID: 33077954. Dataset 2). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Tubulinopathy-associated dysgyria Pathogenic:1

Nov 01, 2021

Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Tubulinopathy Pathogenic:1

Jul 01, 2018

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

A variant that is classified as likely pathogenic has been identified in the TUBA1A gene in a born individual of unknown sex. The c.652G>A, p.(Asp218Asn) variant has been reported as a variant of germline/unknown origin. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.30	T;T;.;T
Eigen	Benign	0.026
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	.;T;T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.5	L;L;.;.
PhyloP100		7.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.0	N;N;N;D
REVEL	Benign	0.25
Sift	Uncertain	0.0050	D;D;.;.
Sift4G	Benign	0.26	T;T;T;.
Polyphen		0.0030	B;B;.;.
Vest4		0.64
MutPred		0.47		Gain of catalytic residue at N216 (P = 0.0057);Gain of catalytic residue at N216 (P = 0.0057);.;.;
MVP		0.73
MPC		1.9
ClinPred		0.90	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.92
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057517858; hg19: chr12-49579497; COSMIC: COSV55497525; COSMIC: COSV55497525;