NM_006009.4:c.246C>T

Variant names:

• chr12-49186439-G-A
• rs1134868
• NM_006009.4:c.246C>T

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.246C>T​(p.Thr82Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 149,558 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000045 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBA1A NM_006009.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.166

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00739038).
• BP6: Variant 12-49186439-G-A is Benign according to our data. Variant chr12-49186439-G-A is described in ClinVar as [Benign]. Clinvar id is 212490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49186439-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.166 with no splicing effect.
• BS2: High AC in GnomAd4 at 258 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA1A	NM_006009.4	c.246C>T	p.Thr82Thr	synonymous_variant	Exon 3 of 4	ENST00000301071.12	NP_006000.2
TUBA1A	NM_001270399.2	c.246C>T	p.Thr82Thr	synonymous_variant	Exon 3 of 4		NP_001257328.1
TUBA1A	NM_001270400.2	c.141C>T	p.Thr47Thr	synonymous_variant	Exon 3 of 4		NP_001257329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12	c.246C>T	p.Thr82Thr	synonymous_variant	Exon 3 of 4	1	NM_006009.4	ENSP00000301071.7

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 260 AN: 149468 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00610

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000793

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.000973

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000446 AC: 65 AN: 1458890 Hom.: 0 Cov.: 46 AF XY: 0.0000372 AC XY: 27 AN XY: 725930

Gnomad4 AFR exome AF: 0.000946

Gnomad4 AMR exome AF: 0.0000897

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.0000998

GnomAD4 genome AF: 0.00173 AC: 258 AN: 149558 Hom.: 0 Cov.: 30 AF XY: 0.00176 AC XY: 129 AN XY: 73134

Gnomad4 AFR AF: 0.00606

Gnomad4 AMR AF: 0.000792

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.000962

Alfa AF: 0.000986 Hom.: 0

ExAC AF: 0.00215 AC: 261

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 30, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 31, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	14
DANN	Benign	0.87
Eigen	Benign	-0.00041
Eigen_PC	Benign	0.0075
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.51	T
PROVEAN	Benign	3.6	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.050	T
Vest4		0.38
MVP		0.79
ClinPred		0.036	T
GERP RS		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1134868; hg19: chr12-49580222;