12-49184799-T-C

Position:

• chr12-49184799-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006009.4(TUBA1A):​c.*211A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 765,496 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0095 (15 hom., cov: 32)
  • Exomes 𝑓: 0.012 (57 hom.)
• Consequence: TUBA1A NM_006009.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.734

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 12-49184799-T-C is Benign according to our data. Variant chr12-49184799-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 309110.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00954 (1453/152242) while in subpopulation NFE AF= 0.0166 (1132/68002). AF 95% confidence interval is 0.0158. There are 15 homozygotes in gnomad4. There are 674 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1453 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.*211A>G		3_prime_UTR_variant	4/4	ENST00000301071.12
TUBA1A	NM_001270399.2	c.*211A>G		3_prime_UTR_variant	4/4
TUBA1A	NM_001270400.2	c.*211A>G		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.*211A>G		3_prime_UTR_variant	4/4	1	NM_006009.4	P1
TUBA1B-AS1	ENST00000656133.1	n.474-3484T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00956 AC: 1455 AN: 152124 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.00544

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00423

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.00431

GnomAD4 exome AF: 0.0124 AC: 7586 AN: 613254 Hom.: 57 Cov.: 8 AF XY: 0.0119 AC XY: 3810 AN XY: 318926

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.00426

Gnomad4 ASJ exome AF: 0.00183

Gnomad4 EAS exome AF: 0.00318

Gnomad4 SAS exome AF: 0.00572

Gnomad4 FIN exome AF: 0.00714

Gnomad4 NFE exome AF: 0.0158

Gnomad4 OTH exome AF: 0.00988

GnomAD4 genome AF: 0.00954 AC: 1453 AN: 152242 Hom.: 15 Cov.: 32 AF XY: 0.00905 AC XY: 674 AN XY: 74450

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.00543

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00424

Gnomad4 SAS AF: 0.00517

Gnomad4 FIN AF: 0.00415

Gnomad4 NFE AF: 0.0166

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.0133 Hom.: 2

Bravo AF: 0.00938

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

Jun 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.84

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: rs140121590; hg19: chr12-49578582;