rs1555162323

Variant names:

• chr12-49185407-C-T
• rs1555162323
• NM_006009.4:c.959G>A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_006009.4(TUBA1A):​c.959G>A​(p.Arg320His) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBA1A NM_006009.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.38

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

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.904
• PP5: Variant 12-49185407-C-T is Pathogenic according to our data. Variant chr12-49185407-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49185407-C-T is described in Lovd as [Pathogenic]. Variant chr12-49185407-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	c.959G>A	p.Arg320His	missense_variant	Exon 4 of 4	ENST00000301071.12	NP_006000.2
TUBA1A	NM_001270399.2	c.959G>A	p.Arg320His	missense_variant	Exon 4 of 4		NP_001257328.1
TUBA1A	NM_001270400.2	c.854G>A	p.Arg285His	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.959G>A	p.Arg320His	missense_variant	Exon 4 of 4	1	NM_006009.4	ENSP00000301071.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Apr 07, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lissencephaly due to TUBA1A mutation Pathogenic:1

Jul 05, 2022

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Dec 01, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; 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: 30744660, 24860126, 35686685, 32732226, 25059107) -

TUBA1A-related disorder Pathogenic:1

Sep 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TUBA1A c.959G>A variant is predicted to result in the amino acid substitution p.Arg320His. This variant has been reported as a de novo variant in multiple individuals with lissencephaly (see for example, Table 1, Bahi-Buisson et al. 2014. PubMed ID: 24860126; Table 1, Lefebvre et al. 2020. PubMed ID: 32732226; Table 1, Weber et al. 2022. PubMed ID: 35686685). 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 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 25 gestational week old fetal individual of male sex. The c.959G>A, p.(Arg320His) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Bahi-Buisson et al. Brain, 2014 PMID: 24860126. HPO-standardized clinical features were: Partial agenesis of the corpus callosum (HP:0001338); Agyria (HP:0031882); Dysgenesis of the cerebellar vermis (HP:0002195); Hypoplasia of the brainstem (HP:0002365); Cerebellar dysplasia (HP:0007033); Gray matter heterotopia (HP:0002281); Microcephaly (HP:0000252) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	.;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.9	H;H;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0070	D;D;.
Sift4G	Benign	0.082	T;T;T
Polyphen		0.66	P;P;.
Vest4		0.86
MutPred		0.70		Gain of catalytic residue at L317 (P = 0.0014);Gain of catalytic residue at L317 (P = 0.0014);.;
MVP		0.93
MPC		4.1
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.84
gMVP		0.99

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

Other links and lift over

dbSNP: rs1555162323; hg19: chr12-49579190; COSMIC: COSV99853818; COSMIC: COSV99853818;