12-49185856-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006009.4(TUBA1A):c.510T>C(p.Ser170Ser) variant causes a synonymous change. The variant allele was found at a frequency of 0.00702 in 1,609,874 control chromosomes in the GnomAD database, including 345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 149 hom., cov: 31)

Exomes 𝑓: 0.0049 ( 196 hom. )

Consequence

TUBA1A
NM_006009.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.87

Variant links:

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 links:

TUBA1B-AS1 (HGNC:56356): (TUBA1B antisense RNA 1)

TUBA1B-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019606948).

BP6

Variant 12-49185856-A-G is Benign according to our data. Variant chr12-49185856-A-G is described in ClinVar as [Benign]. Clinvar id is 137849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49185856-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA1A	NM_006009.4 link	c.510T>C	p.Ser170Ser	synonymous_variant	Exon 4 of 4	ENST00000301071.12	NP_006000.2	Q71U36-1
TUBA1A	NM_001270399.2 link	c.510T>C	p.Ser170Ser	synonymous_variant	Exon 4 of 4		NP_001257328.1	Q71U36-1
TUBA1A	NM_001270400.2 link	c.405T>C	p.Ser135Ser	synonymous_variant	Exon 4 of 4		NP_001257329.1	Q71U36-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12 link	c.510T>C	p.Ser170Ser	synonymous_variant	Exon 4 of 4	1	NM_006009.4	ENSP00000301071.7		Q71U36-1

Frequencies

GnomAD3 genomes

AF:

0.0272

AC:

4137

AN:

151874

Hom.:

144

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0860

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0125

Gnomad ASJ

AF:

0.00434

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00602

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00418

Gnomad OTH

AF:

0.0230

GnomAD3 exomes

AF:

0.00804

AC:

2018

AN:

250856

Hom.:

AF XY:

0.00707

AC XY:

960

AN XY:

135706

show subpopulations

Gnomad AFR exome

AF:

0.0768

Gnomad AMR exome

AF:

0.00390

Gnomad ASJ exome

AF:

0.00378

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00582

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.00358

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00489

AC:

7127

AN:

1457884

Hom.:

196

Cov.:

AF XY:

0.00476

AC XY:

3456

AN XY:

725448

show subpopulations

Gnomad4 AFR exome

AF:

0.0807

Gnomad4 AMR exome

AF:

0.00546

Gnomad4 ASJ exome

AF:

0.00437

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00602

Gnomad4 FIN exome

AF:

0.000861

Gnomad4 NFE exome

AF:

0.00280

Gnomad4 OTH exome

AF:

0.00724

GnomAD4 genome

AF:

0.0274

AC:

4171

AN:

151990

Hom.:

149

Cov.:

AF XY:

0.0273

AC XY:

2025

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0866

Gnomad4 AMR

AF:

0.0124

Gnomad4 ASJ

AF:

0.00434

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00623

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00418

Gnomad4 OTH

AF:

0.0228

Alfa

AF:

0.00388

Hom.:

ESP6500AA

AF:

0.0645

AC:

284

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.0109

AC:

1327

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

TUBA1A-related disorder

Benign:1

Jul 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

9.5

DANN

Benign

0.92

Eigen

Benign

0.014

Eigen_PC

Benign

0.064

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.18

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.82

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.30

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0070

Vest4

0.078

ClinPred

0.044

GERP RS

4.4

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over