12-49185062-ACCT-A

Variant names:

• chr12-49185062-ACCT-A
• rs1555162244
• NM_006009.4:c.1301_1303delAGG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PM4_Supporting

The NM_006009.4(TUBA1A):​c.1301_1303delAGG​(p.Glu434del) variant causes a disruptive inframe deletion 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBA1A NM_006009.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 7.63
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 5 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
• PM4: Nonframeshift variant in NON repetitive region in NM_006009.4. Strenght limited to Supporting due to length of the change: 1aa.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006009.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA1A	NM_006009.4	MANE Select	c.1301_1303delAGG	p.Glu434del	disruptive_inframe_deletion	Exon 4 of 4	NP_006000.2
	TUBA1A	NM_001270399.2		c.1301_1303delAGG	p.Glu434del	disruptive_inframe_deletion	Exon 4 of 4	NP_001257328.1
	TUBA1A	NM_001270400.2		c.1196_1198delAGG	p.Glu399del	disruptive_inframe_deletion	Exon 4 of 4	NP_001257329.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA1A	ENST00000301071.12	TSL:1 MANE Select	c.1301_1303delAGG	p.Glu434del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000301071.7
	TUBA1A	ENST00000550767.6	TSL:1	c.1196_1198delAGG	p.Glu399del	disruptive_inframe_deletion	Exon 5 of 5	ENSP00000446637.1
	TUBA1A	ENST00000295766.9	TSL:2	c.1301_1303delAGG	p.Glu434del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000439020.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jan 15, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Uncertain:1

Apr 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1301_1303delAGG (p.E434del) alteration is located in exon 4 (coding exon 4) of the TUBA1A gene. This alteration consists of an in-frame deletion of 3 nucleotides between nucleotide positions c.1301 and c.1303, resulting in the deletion of 1 residue. Based on data from the Genome Aggregation Database (gnomAD), the TUBA1A c.1301_1303delAGG alteration was not observed, with coverage at this position. The p.E434 amino acid is conserved in available vertebrate species. The p.E434del alteration is predicted to be deleterious with a score of -9.3 by PROVEAN in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Lissencephaly;C0266464:Polymicrogyria Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Likely pathogenic and reported on 12-17-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6

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

Other links and lift over

dbSNP: rs1555162244; hg19: chr12-49578845;