12-49185060-C-G

Variant names:

• chr12-49185060-C-G
• rs1565626860
• NM_006009.4:c.1306G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3 PP5_Moderate

The NM_006009.4(TUBA1A):​c.1306G>C​(p.Gly436Arg) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G436D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBA1A NM_006009.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.53

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-49185059-C-T 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, 0.784
• PP5: Variant 12-49185060-C-G is Pathogenic according to our data. Variant chr12-49185060-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 625497.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-49185060-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA1A	NM_006009.4	c.1306G>C	p.Gly436Arg	missense_variant	Exon 4 of 4	ENST00000301071.12	NP_006000.2
TUBA1A	NM_001270399.2	c.1306G>C	p.Gly436Arg	missense_variant	Exon 4 of 4		NP_001257328.1
TUBA1A	NM_001270400.2	c.1201G>C	p.Gly401Arg	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.1306G>C	p.Gly436Arg	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

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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 7 years old born individual of male sex. The c.1306G>C, p.(Gly436Arg) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Bahi-Buisson et al. J Med Genet, 2008 PMID: 18728072. HPO-standardized clinical features were: Hypoplasia of the corpus callosum (HP:0002079); Pachygyria (HP:0001302); Cerebellar vermis hypoplasia (HP:0001320); Hypoplasia of the brainstem (HP:0002365); Abnormality of the internal capsule (HP:0012502); Microcephaly (HP:0000252); Spasticity (HP:0001257); no Seizures (-HP:0001250); Strabismus (HP:0000486) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Uncertain	0.55	D;D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	.;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.4	M;M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.58
MutPred		0.29		Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);.;
MVP		0.92
MPC		2.1
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.87
gMVP		0.95

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: rs1565626860; hg19: chr12-49578843;