12-49188973-TC-T

Position:

• chr12-49188973-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_006009.4(TUBA1A):​c.3+3del variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBA1A NM_006009.4 splice_donor_region, intron
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.441

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]

TUBA1C (HGNC:20768): (tubulin alpha 1c) Predicted to enable GTP binding activity. Predicted to be a structural constituent of cytoskeleton. Predicted to be involved in microtubule cytoskeleton organization and mitotic cell cycle. Located in microtubule cytoskeleton and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-49188973-TC-T is Pathogenic according to our data. Variant chr12-49188973-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1064595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49188973-TC-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.3+3del		splice_donor_region_variant, intron_variant		ENST00000301071.12
TUBA1A	NM_001270399.2	c.-555del		5_prime_UTR_variant	1/4
TUBA1A	NM_001270400.2	c.-188del		5_prime_UTR_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.3+3del		splice_donor_region_variant, intron_variant		1	NM_006009.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lissencephaly due to TUBA1A mutation Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0209 - Splice variant (canonical or non-canonical) proven to affect splicing/expression of the transcript with uncertain effect on protein structure. RT-PCR studies have shown that this variant results in loss of the main isoform in brain and the use of an alternative criptic site. This is predicted to result in a deletion of the first 35 residues of the protein, p.(Met1_Gln35del) (personal communication). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - A nucleotide change at the same position has been observed in gnomAD (2 heterozygous, 0 homozygous). (N) 0508 - In silico predictions for abnormal splicing are conflicting. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1204 - Variant shown to be de novo in proband (parental status not tested but assumed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kids Neuroscience Centre, Sydney Children's Hospitals Network	-	The vast majority of transcripts derived from c.3+3del variant allele use the least frequently utilized 5’-splice site at Chr12:g.49582671 for exon 1-2 splicing, removing 35 highly conserved amino acids from the N-terminus of tubulin alpha 1-A chain (Figure 6). The overall consequence of the c.3+3del variant is loss of expression of the predominant TUBA1A isoform expressed in brain and all tissues examined, which is likely to be associated with haploinsufficiency of the predominant isoform of Tubulin alpha-1A chain. It is clear the encoded 35 residues encoded in this isoform are functionally important, with 7 of these 35 amino acids are classified as pathogenic variants associated with lissencephaly in ClinVar or LOVD. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.41		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-49582756;