rs387906840

Variant names:

• chr12-49186824-T-G
• rs387906840
• NM_006009.4:c.13A>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_006009.4(TUBA1A):​c.13A>C​(p.Ile5Leu) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBA1A NM_006009.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.93

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 Uncertain_significance. Variant got 5 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.
• PP5: Variant 12-49186824-T-G is Pathogenic according to our data. Variant chr12-49186824-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30268.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-49186824-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA1A	NM_006009.4	c.13A>C	p.Ile5Leu	missense_variant	Exon 2 of 4	ENST00000301071.12	NP_006000.2
TUBA1A	NM_001270399.2	c.13A>C	p.Ile5Leu	missense_variant	Exon 2 of 4		NP_001257328.1
TUBA1A	NM_001270400.2	c.-93A>C		5_prime_UTR_variant	Exon 2 of 4		NP_001257329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12	c.13A>C	p.Ile5Leu	missense_variant	Exon 2 of 4	1	NM_006009.4	ENSP00000301071.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Lissencephaly due to TUBA1A mutation Pathogenic:1

Mar 15, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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 7 years old born individual of female sex. The c.13A>C, p.(Ile5Leu) variant has been reported as a variant of germline origin. This variant and associated phenotype was previously reported by Jansen et al. Neurology, 2011 PMID: 21403111. HPO-standardized clinical features were: Hypoplasia of the corpus callosum (HP:0002079); Perisylvian polymicrogyria (HP:0012650); no Abnormality of the cerebellar vermis (-HP:0002334); Hypoplasia of the brainstem (HP:0002365); Gray matter heterotopia (HP:0002281); Abnormality of the internal capsule (HP:0012502); Microcephaly (HP:0000252); Spasticity (HP:0001257); Focal seizures (HP:0007359); Strabismus (HP:0000486) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Benign	0.18	T;T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	.;T;T
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.8	L;L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.0	N;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.043	D;D;D
Sift4G	Benign	0.15	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.70
MutPred		0.56		Gain of catalytic residue at I5 (P = 0);Gain of catalytic residue at I5 (P = 0);Gain of catalytic residue at I5 (P = 0);
MVP		0.97
MPC		2.0
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.68
gMVP		0.98

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: rs387906840; hg19: chr12-49580607;