chr12-49185063-CCTCCTCATAATCCTT-C

Variant names:

• chr12-49185063-CCTCCTCATAATCCTT-C
• rs2121241118
• NM_006009.4:c.1288_1302delAAGGATTATGAGGAG

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM4 PP3 PP5_Moderate

The NM_006009.4(TUBA1A):​c.1288_1302delAAGGATTATGAGGAG​(p.Lys430_Glu434del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBA1A NM_006009.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.87
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006009.4
• PM4: Nonframeshift variant in NON repetitive region in NM_006009.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 12-49185063-CCTCCTCATAATCCTT-C is Pathogenic according to our data. Variant chr12-49185063-CCTCCTCATAATCCTT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1065497.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA1A	NM_006009.4	MANE Select	c.1288_1302delAAGGATTATGAGGAG	p.Lys430_Glu434del	conservative_inframe_deletion	Exon 4 of 4	NP_006000.2
	TUBA1A	NM_001270399.2		c.1288_1302delAAGGATTATGAGGAG	p.Lys430_Glu434del	conservative_inframe_deletion	Exon 4 of 4	NP_001257328.1	Q71U36-1
	TUBA1A	NM_001270400.2		c.1183_1197delAAGGATTATGAGGAG	p.Lys395_Glu399del	conservative_inframe_deletion	Exon 4 of 4	NP_001257329.1	Q71U36-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA1A	ENST00000301071.12	TSL:1 MANE Select	c.1288_1302delAAGGATTATGAGGAG	p.Lys430_Glu434del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000301071.7	Q71U36-1
	TUBA1A	ENST00000550767.6	TSL:1	c.1183_1197delAAGGATTATGAGGAG	p.Lys395_Glu399del	conservative_inframe_deletion	Exon 5 of 5	ENSP00000446637.1	Q71U36-2
	TUBA1A	ENST00000295766.9	TSL:2	c.1288_1302delAAGGATTATGAGGAG	p.Lys430_Glu434del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000439020.2	Q71U36-1

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Lissencephaly due to TUBA1A mutation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9

Splicing

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

Other links and lift over

dbSNP: rs2121241118; hg19: chr12-49578846;