12-49188874-G-A

Position:

• chr12-49188874-G-A

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+103C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0482 in 1,612,362 control chromosomes in the GnomAD database, including 2,275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (127 hom., cov: 32)
  • Exomes 𝑓: 0.049 (2148 hom.)
• Consequence: TUBA1A NM_006009.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.991

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=-0.86).
• BP6: Variant 12-49188874-G-A is Benign according to our data. Variant chr12-49188874-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1207784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.3+103C>T		intron_variant		ENST00000301071.12
TUBA1A	NM_001270399.2	c.-455C>T		5_prime_UTR_variant	1/4
TUBA1A	NM_001270400.2	c.-103+15C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.3+103C>T		intron_variant		1	NM_006009.4	P1

Frequencies

GnomAD3 genomes AF: 0.0367 AC: 5576 AN: 152126 Hom.: 127 Cov.: 32

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.0476

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0440

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0546

Gnomad OTH AF: 0.0444

GnomAD4 exome AF: 0.0495 AC: 72210 AN: 1460118 Hom.: 2148 Cov.: 33 AF XY: 0.0486 AC XY: 35287 AN XY: 726368

Gnomad4 AFR exome AF: 0.00887

Gnomad4 AMR exome AF: 0.0326

Gnomad4 ASJ exome AF: 0.0210

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00739

Gnomad4 FIN exome AF: 0.0388

Gnomad4 NFE exome AF: 0.0578

Gnomad4 OTH exome AF: 0.0456

GnomAD4 genome AF: 0.0366 AC: 5574 AN: 152244 Hom.: 127 Cov.: 32 AF XY: 0.0363 AC XY: 2701 AN XY: 74438

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.0475

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.0440

Gnomad4 NFE AF: 0.0546

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0339 Hom.: 39

Bravo AF: 0.0366

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.4
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35896524; hg19: chr12-49582657;