12-49188909-T-G

Position:

• chr12-49188909-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006009.4(TUBA1A):​c.3+68A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,613,412 control chromosomes in the GnomAD database, including 103,113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8565 hom., cov: 32)
  • Exomes 𝑓: 0.35 (94548 hom.)
• Consequence: TUBA1A NM_006009.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.20

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-49188909-T-G is Benign according to our data. Variant chr12-49188909-T-G is described in ClinVar as [Benign]. Clinvar id is 1238419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.3+68A>C		intron_variant		ENST00000301071.12
TUBA1A	NM_001270399.2	c.-490A>C		5_prime_UTR_variant	1/4
TUBA1A	NM_001270400.2	c.-123A>C		5_prime_UTR_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.3+68A>C		intron_variant		1	NM_006009.4	P1

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48569 AN: 151690 Hom.: 8563 Cov.: 32

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.311

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.715

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.308

GnomAD4 exome AF: 0.350 AC: 512081 AN: 1461604 Hom.: 94548 Cov.: 56 AF XY: 0.353 AC XY: 256967 AN XY: 727096

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.319

Gnomad4 ASJ exome AF: 0.242

Gnomad4 EAS exome AF: 0.714

Gnomad4 SAS exome AF: 0.472

Gnomad4 FIN exome AF: 0.403

Gnomad4 NFE exome AF: 0.334

Gnomad4 OTH exome AF: 0.351

GnomAD4 genome AF: 0.320 AC: 48586 AN: 151808 Hom.: 8565 Cov.: 32 AF XY: 0.328 AC XY: 24339 AN XY: 74176

Gnomad4 AFR AF: 0.223

Gnomad4 AMR AF: 0.311

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.715

Gnomad4 SAS AF: 0.505

Gnomad4 FIN AF: 0.409

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.306

Alfa AF: 0.318 Hom.: 9018

Bravo AF: 0.305

Asia WGS AF: 0.557 AC: 1934 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.4
DANN	Benign	0.55

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: rs1039225; hg19: chr12-49582692;