rs61730859

Positions:

• chr12-49185844-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.522G>A​(p.Ala174=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00694 in 1,610,752 control chromosomes in the GnomAD database, including 332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (150 hom., cov: 31)
  • Exomes 𝑓: 0.0048 (182 hom.)
• Consequence: TUBA1A NM_006009.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.240

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=0.0014648736).
• BP6: Variant 12-49185844-C-T is Benign according to our data. Variant chr12-49185844-C-T is described in ClinVar as [Benign]. Clinvar id is 137850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49185844-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBA1A	NM_006009.4	c.522G>A	p.Ala174=	synonymous_variant	4/4	ENST00000301071.12	NP_006000.2
TUBA1A	NM_001270399.2	c.522G>A	p.Ala174=	synonymous_variant	4/4		NP_001257328.1
TUBA1A	NM_001270400.2	c.417G>A	p.Ala139=	synonymous_variant	4/4		NP_001257329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12	c.522G>A	p.Ala174=	synonymous_variant	4/4	1	NM_006009.4	ENSP00000301071	P1
TUBA1B-AS1	ENST00000656133.1	n.474-2439C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 4082 AN: 151800 Hom.: 145 Cov.: 31

Gnomad AFR AF: 0.0859

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00387

Gnomad OTH AF: 0.0216

GnomAD3 exomes AF: 0.00830 AC: 2084 AN: 251170 Hom.: 73 AF XY: 0.00699 AC XY: 950 AN XY: 135832

Gnomad AFR exome AF: 0.0830

Gnomad AMR exome AF: 0.00385

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00395

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00362

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00484 AC: 7065 AN: 1458836 Hom.: 182 Cov.: 30 AF XY: 0.00459 AC XY: 3335 AN XY: 725830

Gnomad4 AFR exome AF: 0.0826

Gnomad4 AMR exome AF: 0.00535

Gnomad4 ASJ exome AF: 0.00444

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00370

Gnomad4 FIN exome AF: 0.000805

Gnomad4 NFE exome AF: 0.00288

Gnomad4 OTH exome AF: 0.00692

GnomAD4 genome AF: 0.0271 AC: 4116 AN: 151916 Hom.: 150 Cov.: 31 AF XY: 0.0268 AC XY: 1991 AN XY: 74242

Gnomad4 AFR AF: 0.0865

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00387

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.00917 Hom.: 11

ESP6500AA AF: 0.0749 AC: 330

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.0105 AC: 1275

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	12
DANN	Benign	0.83
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;N
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.080
ClinPred		0.030	T
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

Other links and lift over

dbSNP: rs61730859; hg19: chr12-49579627;