12-49185101-C-T

Position:

• chr12-49185101-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_006009.4(TUBA1A):​c.1265G>A​(p.Arg422His) variant causes a missense change. 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. R422C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBA1A NM_006009.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 5.82

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 19 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 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 chr12-49185102-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 12-49185101-C-T is Pathogenic according to our data. Variant chr12-49185101-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49185101-C-T is described in Lovd as [Pathogenic]. Variant chr12-49185101-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.1265G>A	p.Arg422His	missense_variant	4/4	ENST00000301071.12
TUBA1A	NM_001270399.2	c.1265G>A	p.Arg422His	missense_variant	4/4
TUBA1A	NM_001270400.2	c.1160G>A	p.Arg387His	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.1265G>A	p.Arg422His	missense_variant	4/4	1	NM_006009.4	P1
TUBA1B-AS1	ENST00000656133.1	n.474-3182C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lissencephaly due to TUBA1A mutation Pathogenic:5 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Service de Génétique Moléculaire, Hôpital Robert Debré	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	not provided	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	-	- -
not provided, no classification provided	literature only	GeneReviews	-	Classic lissencephaly -
Pathogenic, criteria provided, single submitter	research	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	-	Analysis of the exome sequencing data showed a heterozygous sequence variant in TUBA1A gene. This variant is predicted as Disease Causing by MutationTaster. Sanger sequencing confirmed the variation in the proband. Parents were homozygous for the wildtype allele. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 03, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg422 amino acid residue in TUBA1A. Other variant(s) that disrupt this residue have been observed in individuals with TUBA1A-related conditions (PMID: 18728072), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 7077). This missense change has been observed in individual(s) with cortical malformations (PMID: 18728072, 20466733, 26350204, 29671837). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 422 of the TUBA1A protein (p.Arg422His). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2021	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21875651, 25059107, 24860126, 22264709, 18669490, 29671837, 20466733, 26350204, 18954413, 20376468, 22948023, 18728072, 33453472, 30744660) -

Lissencephaly Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

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 9 years old born individual of male sex. The c.1265G>A, p.(Arg422His) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Morris-Rosendahl et al. Clin Genet, 2008 PMID: 18954413. HPO-standardized clinical features were: Partial agenesis of the corpus callosum (HP:0001338); Pachygyria (HP:0001302); Cerebellar vermis hypoplasia (HP:0001320); Hypoplasia of the pons (HP:0012110); Dysgenesis of the hippocampus (HP:0025101); Dilation of lateral ventricles, Dilated fourth ventricle (HP:0006956, HP:0002198); Gray matter heterotopia (HP:0002281); Congenital microcephaly (HP:0011451); Microcephaly (HP:0000252); Muscular hypotonia (HP:0001252); Generalized tonic-clonic seizures (HP:0002069) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.54	D;D;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.9	H;H;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.030	D;D;D
Polyphen		0.22	B;B;.
Vest4		0.83
MutPred		0.86		Gain of catalytic residue at R422 (P = 0.1599);Gain of catalytic residue at R422 (P = 0.1599);.;
MVP		0.97
MPC		4.2
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.78
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: rs137853050; hg19: chr12-49578884; COSMIC: COSV99853833; COSMIC: COSV99853833;