rs863224938

Positions:

• chr12-49186333-C-G
• chr12-49186333-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP5_Very_Strong

The NM_006009.4(TUBA1A):​c.352G>C​(p.Val118Leu) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V118M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBA1A NM_006009.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.56

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 15 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 chr12-49186333-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, TUBA1A
• PP5: Variant 12-49186333-C-G is Pathogenic according to our data. Variant chr12-49186333-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 625508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49186333-C-G is described in Lovd as [Likely_pathogenic]. Variant chr12-49186333-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.352G>C	p.Val118Leu	missense_variant	3/4	ENST00000301071.12
TUBA1A	NM_001270399.2	c.352G>C	p.Val118Leu	missense_variant	3/4
TUBA1A	NM_001270400.2	c.247G>C	p.Val83Leu	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.352G>C	p.Val118Leu	missense_variant	3/4	1	NM_006009.4	P1
TUBA1B-AS1	ENST00000656133.1	n.474-1950C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TUBA1A-associated tubulinopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This variant has been previously reported as a de novo change in a 3 years-old boy with delayed development, spastic tetraparesis, severe ID, congenital microcephaly and focal seizures (PMID: 28677066). A different missense variant affecting the same amino acid residue (c.352G>A, p.Val118Met) has been previously reported in a 4 year-old individual with astigmatism, early tooth eruption, premature adult teeth, brain malformation, developmental delay, spasticity, hyperreflexia and wide based gait (PMID: 25326637). The TUBA1A gene is constrained against variation (Z-score= 5.58 and pLI = 0.97), and missense variants have been reported in individuals with TUBA1A-associated tubulinopathy (HGMD, ClinVar database; PMID: 24860126, 28677066, 25326637). The c.352G>C variant is absent from the gnomAD population database and thus is presumed to be rare. The c.352G>C variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.352G>C variant is classified as Pathogenic. -

Tubulinopathy Pathogenic:1

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 pathogenic has been identified in the TUBA1A gene in a 30 months old born individual of male sex. The c.352G>C, p.(Val118Leu) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Romaniello et al. Eur Radiol, 2017 PMID: 28677066. HPO-standardized clinical features were: Agenesis of the corpus callosum (HP:0001274); Cortical gyral simplification (HP:0009879); Dysgenesis of the cerebellar vermis (HP:0002195); Brainstem dysplasia (HP:0002508); Dilated fourth ventricle (HP:0002198); Abnormality of the internal capsule (HP:0012502); Congenital microcephaly (HP:0011451); Spasticity (HP:0001257); Focal seizures (HP:0007359) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.28	T;T;.;T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.67	D;D;D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.6	M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.6	N;N;N;N;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;D;.;.;.
Sift4G	Uncertain	0.044	D;D;D;.;T
Polyphen		0.0040	B;B;.;.;.
Vest4		0.54
MutPred		0.40		Gain of catalytic residue at L119 (P = 0.0085);Gain of catalytic residue at L119 (P = 0.0085);.;.;.;
MVP		0.87
MPC		2.1
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.88
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: rs863224938; hg19: chr12-49580116;