rs587784489

Positions:

• chr12-49185845-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP5

The ENST00000301071.12(TUBA1A):​c.521C>T​(p.Ala174Val) 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. A174P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TUBA1A ENST00000301071.12 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:2
• Conservation: PhyloP100: 9.46

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.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000301071.12
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-49185846-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 546297.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBA1A. . Gene score misZ 5.584 (greater than the threshold 3.09). Trascript score misZ 8.7455 (greater than threshold 3.09). GenCC has associacion of gene with tubulinopathy-associated dysgyria, intellectual disability, autosomal dominant 40, tubulinopathy, lissencephaly due to TUBA1A mutation.
• PP5: Variant 12-49185845-G-A is Pathogenic according to our data. Variant chr12-49185845-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 160159.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Pathogenic=3, Uncertain_significance=2}. Variant chr12-49185845-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBA1A	NM_006009.4	c.521C>T	p.Ala174Val	missense_variant	4/4	ENST00000301071.12	NP_006000.2
TUBA1A	NM_001270399.2	c.521C>T	p.Ala174Val	missense_variant	4/4		NP_001257328.1
TUBA1A	NM_001270400.2	c.416C>T	p.Ala139Val	missense_variant	4/4		NP_001257329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12	c.521C>T	p.Ala174Val	missense_variant	4/4	1	NM_006009.4	ENSP00000301071	P1
TUBA1B-AS1	ENST00000656133.1	n.474-2438G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lissencephaly due to TUBA1A mutation Pathogenic:4 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 11, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 21, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 19, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 29, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Oct 16, 2023	- -

not provided Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 24860126, 32978145, 30744660, 31833200) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 11, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 174 of the TUBA1A protein (p.Ala174Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of TUBA1A-related conditions (PMID: 31833200; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 160159). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Early myoclonic encephalopathy;C3806403:Continuous spike and waves during slow sleep;C5568850:Tubulinopathy-associated dysgyria Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg

Nov 01, 2021

- -

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.521C>T, p.(Ala174Val) variant has been reported as a variant of germline/unknown origin. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;D;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	.;T;T;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Uncertain	-0.0077	T
MutationAssessor	Pathogenic	3.4	M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.5	D;D;D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Uncertain	0.051	T;T;T;.
Polyphen		0.99	D;D;.;.
Vest4		0.73
MutPred		0.35		Gain of catalytic residue at Q176 (P = 0);Gain of catalytic residue at Q176 (P = 0);.;.;
MVP		0.84
MPC		3.3
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.97

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: rs587784489; hg19: chr12-49579628;