12-49188808-T-TGCG

Position:

• chr12-49188808-T-TGCG

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_006009.4(TUBA1A):​c.3+168_3+169insCGC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0056 in 1,596,230 control chromosomes in the GnomAD database, including 37 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0055 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (26 hom.)
• Consequence: TUBA1A NM_006009.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.00

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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 12-49188808-T-TGCG is Benign according to our data. Variant chr12-49188808-T-TGCG is described in ClinVar as [Likely_benign]. Clinvar id is 1200928.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 845 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.3+168_3+169insCGC		intron_variant		ENST00000301071.12
TUBA1A	NM_001270399.2	c.-390_-389insCGC		5_prime_UTR_variant	1/4
TUBA1A	NM_001270400.2	c.-103+80_-103+81insCGC		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.3+168_3+169insCGC		intron_variant		1	NM_006009.4	P1

Frequencies

GnomAD3 genomes AF: 0.00555 AC: 845 AN: 152226 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0285

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00616

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.00560 AC: 8087 AN: 1443886 Hom.: 26 Cov.: 32 AF XY: 0.00560 AC XY: 4022 AN XY: 718430

Gnomad4 AFR exome AF: 0.000722

Gnomad4 AMR exome AF: 0.00301

Gnomad4 ASJ exome AF: 0.00316

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00601

Gnomad4 FIN exome AF: 0.0292

Gnomad4 NFE exome AF: 0.00519

Gnomad4 OTH exome AF: 0.00625

GnomAD4 genome AF: 0.00555 AC: 845 AN: 152344 Hom.: 11 Cov.: 32 AF XY: 0.00639 AC XY: 476 AN XY: 74500

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.0285

Gnomad4 NFE AF: 0.00616

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00621 Hom.: 1

Bravo AF: 0.00329

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 24, 2018

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs560742601; hg19: chr12-49582591;