chr12-49185110-G-A

Position:

• chr12-49185110-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_006009.4(TUBA1A):​c.1256C>T​(p.Ser419Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S419S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBA1A NM_006009.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.51

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 14 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, 5 uncertain in NM_006009.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.761
• PP5: Variant 12-49185110-G-A is Pathogenic according to our data. Variant chr12-49185110-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49185110-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.1256C>T	p.Ser419Leu	missense_variant	4/4	ENST00000301071.12
TUBA1A	NM_001270399.2	c.1256C>T	p.Ser419Leu	missense_variant	4/4
TUBA1A	NM_001270400.2	c.1151C>T	p.Ser384Leu	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.1256C>T	p.Ser419Leu	missense_variant	4/4	1	NM_006009.4	P1
TUBA1B-AS1	ENST00000656133.1	n.474-3173G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lissencephaly due to TUBA1A mutation Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 22, 2022	This variant was identified as de novo mosaic (maternity and paternity confirmed)._x000D_ Criteria applied: PS2, PS4_MOD, PM1, PM2_SUP, PP3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 15, 2010	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2021

- -

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 2 years old born individual of male sex. The c.1256C>T, p.(Ser419Leu) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Poirier et al. Hum Mutat, 2007 PMID: 17584854. HPO-standardized clinical features were: Dysplastic corpus callosum (HP:0006989); Pachygyria (HP:0001302); Cerebellar vermis hypoplasia (HP:0001320); no Abnormality of brainstem morphology (-HP:0002363); Dysgenesis of the hippocampus (HP:0025101); Dilation of lateral ventricles (HP:0006956); Gray matter heterotopia (HP:0002281); no Congenital microcephaly (-HP:0011451); no Microcephaly (-HP:0000252); Spasticity (HP:0001257); Generalized tonic-clonic seizures (HP:0002069) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Uncertain	0.50	T;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	.;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Uncertain	-0.029	T
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D;.
Sift4G	Benign	0.077	T;T;T
Polyphen		0.0020	B;B;.
Vest4		0.70
MutPred		0.69		Loss of phosphorylation at S419 (P = 0.0073);Loss of phosphorylation at S419 (P = 0.0073);.;
MVP		0.93
MPC		1.7
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.77
gMVP		0.91

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: rs137853047; hg19: chr12-49578893;