12-49185558-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP5_Moderate

The NM_006009.4(TUBA1A):c.808G>A(p.Ala270Thr) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A270S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TUBA1A NM_006009.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.26

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 9 ACMG points.

• PM1: In a hotspot region, there are 5 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 chr12-49185558-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 160164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, TUBA1A
• PP5: Variant 12-49185558-C-T is Pathogenic according to our data. Variant chr12-49185558-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 625500.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-49185558-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.808G>A	p.Ala270Thr	missense_variant	4/4	ENST00000301071.12
TUBA1A	NM_001270399.2	c.808G>A	p.Ala270Thr	missense_variant	4/4
TUBA1A	NM_001270400.2	c.703G>A	p.Ala235Thr	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.808G>A	p.Ala270Thr	missense_variant	4/4	1	NM_006009.4	P1
TUBA1B-AS1	ENST00000656133.1	n.474-2725C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tubulinopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only

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

Jul 01, 2018

A variant that is classified as likely pathogenic has been identified in the TUBA1A gene in a born individual of unknown sex. The c.808G>A, p.(Ala270Thr) variant has been reported as a variant of unknown origin. This variant and associated phenotype was previously reported by Kumar et al. Hum Mol Genet, 2010 PMID: 20466733. HPO-standardized clinical features were: Agenesis of the corpus callosum (HP:0001274); Pachygyria (HP:0001302); Cerebellar vermis hypoplasia (HP:0001320); Hypoplasia of the brainstem (HP:0002365); Cerebellar hypoplasia (HP:0001321); Dysgenesis of the hippocampus (HP:0025101); Dilated fourth ventricle (HP:0002198) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Uncertain	23
Dann	Benign	0.93
DEOGEN2	Benign	0.28	T;T;.
Eigen	Benign	0.034
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.65	N;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0070	D;D;.
Sift4G	Benign	0.46	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.73
MutPred		0.30		Gain of catalytic residue at F267 (P = 0.0016);Gain of catalytic residue at F267 (P = 0.0016);.;
MVP		0.96
MPC		1.9
ClinPred		0.89	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
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

Other links and lift over

dbSNP: rs587784494; hg19: chr12-49579341;