rs697624

chr12-49185913-C-Gchr12-49185913-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006009.4(TUBA1A):c.453G>C(p.Ser151=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 1,612,662 control chromosomes in the GnomAD database, including 126,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S151S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.45 (17126 hom., cov: 30)
  • Exomes 𝑓: 0.38 (108876 hom.)
• Consequence: TUBA1A NM_006009.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.300

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1844239E-5).
• BP6: Variant 12-49185913-C-G is Benign according to our data. Variant chr12-49185913-C-G is described in ClinVar as [Benign]. Clinvar id is 160157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49185913-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA1A	NM_006009.4	c.453G>C	p.Ser151=	synonymous_variant	4/4	ENST00000301071.12
TUBA1A	NM_001270399.2	c.453G>C	p.Ser151=	synonymous_variant	4/4
TUBA1A	NM_001270400.2	c.348G>C	p.Ser116=	synonymous_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA1A	ENST00000301071.12	c.453G>C	p.Ser151=	synonymous_variant	4/4	1	NM_006009.4	P1
TUBA1B-AS1	ENST00000656133.1	n.474-2370C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68608 AN: 151586 Hom.: 17079 Cov.: 30

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.223

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.345

Gnomad OTH AF: 0.417

GnomAD3 exomes AF: 0.416 AC: 104302 AN: 250668 Hom.: 23555 AF XY: 0.416 AC XY: 56424 AN XY: 135530

Gnomad AFR exome AF: 0.649

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.268

Gnomad EAS exome AF: 0.736

Gnomad SAS exome AF: 0.523

Gnomad FIN exome AF: 0.403

Gnomad NFE exome AF: 0.341

Gnomad OTH exome AF: 0.382

GnomAD4 exome AF: 0.377 AC: 550350 AN: 1460954 Hom.: 108876 Cov.: 76 AF XY: 0.379 AC XY: 275721 AN XY: 726792

Gnomad4 AFR exome AF: 0.655

Gnomad4 AMR exome AF: 0.353

Gnomad4 ASJ exome AF: 0.275

Gnomad4 EAS exome AF: 0.715

Gnomad4 SAS exome AF: 0.520

Gnomad4 FIN exome AF: 0.404

Gnomad4 NFE exome AF: 0.347

Gnomad4 OTH exome AF: 0.393

GnomAD4 genome AF: 0.453 AC: 68717 AN: 151708 Hom.: 17126 Cov.: 30 AF XY: 0.457 AC XY: 33894 AN XY: 74092

Gnomad4 AFR AF: 0.648

Gnomad4 AMR AF: 0.376

Gnomad4 ASJ AF: 0.269

Gnomad4 EAS AF: 0.721

Gnomad4 SAS AF: 0.550

Gnomad4 FIN AF: 0.412

Gnomad4 NFE AF: 0.345

Gnomad4 OTH AF: 0.417

Alfa AF: 0.317 Hom.: 2394

Bravo AF: 0.454

TwinsUK AF: 0.336 AC: 1245

ALSPAC AF: 0.358 AC: 1379

ESP6500AA AF: 0.642 AC: 2830

ESP6500EA AF: 0.329 AC: 2826

ExAC AF: 0.421 AC: 51082

EpiCase AF: 0.337

EpiControl AF: 0.328

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Lissencephaly due to TUBA1A mutation Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

TUBA1A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2021

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	-0.38	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	7.4
Dann	Benign	0.71
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.000012	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.93	P;P;P;P;P;P;P
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.044
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.32	T
Vest4		0.081
ClinPred		0.011	T
GERP RS		0.17

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: rs697624; hg19: chr12-49579696; COSMIC: COSV55496973; COSMIC: COSV55496973;