rs762008241

Positions:

• chr12-49185580-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006009.4(TUBA1A):​c.786T>C​(p.Tyr262Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0009 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00035 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBA1A NM_006009.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.396

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]

TUBA1A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 12-49185580-A-G is Benign according to our data. Variant chr12-49185580-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 212493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49185580-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.396 with no splicing effect.
• BS2: High AC in GnomAd4 at 137 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBA1A	NM_006009.4	c.786T>C	p.Tyr262Tyr	synonymous_variant	4/4	ENST00000301071.12	NP_006000.2
TUBA1A	NM_001270399.2	c.786T>C	p.Tyr262Tyr	synonymous_variant	4/4		NP_001257328.1
TUBA1A	NM_001270400.2	c.681T>C	p.Tyr227Tyr	synonymous_variant	4/4		NP_001257329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12	c.786T>C	p.Tyr262Tyr	synonymous_variant	4/4	1	NM_006009.4	ENSP00000301071.7

Frequencies

GnomAD3 genomes AF: 0.000901 AC: 137 AN: 152096 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000478

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000350 AC: 511 AN: 1461246 Hom.: 1 Cov.: 30 AF XY: 0.000367 AC XY: 267 AN XY: 726936

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.000808

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000305

Gnomad4 OTH exome AF: 0.000514

GnomAD4 genome AF: 0.000900 AC: 137 AN: 152214 Hom.: 0 Cov.: 31 AF XY: 0.000981 AC XY: 73 AN XY: 74450

Gnomad4 AFR AF: 0.00202

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000578

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000393 Hom.: 0

Bravo AF: 0.000858

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 28, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.6
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs762008241; hg19: chr12-49579363; COSMIC: COSV55497241; COSMIC: COSV55497241;