12-49185102-G-A

Position:

• chr12-49185102-G-A

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.1264C>T​(p.Arg422Cys) 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. R422H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TUBA1A NM_006009.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.84

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 chr12-49185101-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.
• 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 12-49185102-G-A is Pathogenic according to our data. 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. Variant chr12-49185102-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.1264C>T	p.Arg422Cys	missense_variant	4/4	ENST00000301071.12
TUBA1A	NM_001270399.2	c.1264C>T	p.Arg422Cys	missense_variant	4/4
TUBA1A	NM_001270400.2	c.1159C>T	p.Arg387Cys	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.1264C>T	p.Arg422Cys	missense_variant	4/4	1	NM_006009.4	P1
TUBA1B-AS1	ENST00000656133.1	n.474-3181G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lissencephaly due to TUBA1A mutation Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	Classification according to ACMG guidelines of c.1264C>T:p.(Arg422Cys) in TUBA1A: pathogenic. - PS2: new mutation (further independent validation is pending). - PM1: the variant is located in a mutation hotspot and/or a critical and well established functional domain - PM2: The variant has not been identified in any population genetic studies (such as GnomAD, Iranome, GME, 1kGP, etc.) identified. - PP2: sense-changing variant in a gene that has a low rate of benign sense-changing variants and in which sense-changing variants are a common disease mechanism. are. - PP3: Bioinformatics prediction programs classify this variant as pathogenic. The gene TUBA1A codes for tubulin alpha 1a, which is particularly expressed in the brain. The TUBA1A-associated tubulinopathy (lissencephaly) is an autosomal dominant and clinically very in which brain malformations, microcephaly, developmental delay, and epilepsy are the main clinical and epilepsy, mainly caused by new mutations in TUBA1A. The new mutation c.1264C>T:p.(Arg422Cys) has been described several times in patients with lissencephaly. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 19, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20466733, 18728072, 20376468, 22264709, 28412269, 24860126, 30744660, 33064843, 36028527, 24077912, 27535533) -

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 54 months old born individual of female sex. The c.1264C>T, p.(Arg422Cys) 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); Abnormality of the internal capsule (HP:0012502); Microcephaly (HP:0000252); Spasticity (HP:0001257); no Seizures (-HP:0001250) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	2.9	M;M;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;.
Sift4G	Benign	0.088	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.84
MutPred		0.85		Loss of disorder (P = 0.111);Loss of disorder (P = 0.111);.;
MVP		0.96
MPC		4.3
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.78
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: rs137853049; hg19: chr12-49578885; COSMIC: COSV55497560; COSMIC: COSV55497560;