rs142641191

Positions:

• chr12-49185400-G-A

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.966C>T​(p.Asp322=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00329 in 1,614,066 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (16 hom.)
• Consequence: TUBA1A NM_006009.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.53

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 (BayesDel_noAF=-0.53).
• BP6: Variant 12-49185400-G-A is Benign according to our data. Variant chr12-49185400-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 160165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49185400-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.53 with no splicing effect.
• BS2: High AC in GnomAd4 at 379 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBA1A	NM_006009.4	c.966C>T	p.Asp322=	synonymous_variant	4/4	ENST00000301071.12	NP_006000.2
TUBA1A	NM_001270399.2	c.966C>T	p.Asp322=	synonymous_variant	4/4		NP_001257328.1
TUBA1A	NM_001270400.2	c.861C>T	p.Asp287=	synonymous_variant	4/4		NP_001257329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12	c.966C>T	p.Asp322=	synonymous_variant	4/4	1	NM_006009.4	ENSP00000301071	P1
TUBA1B-AS1	ENST00000656133.1	n.474-2883G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 379 AN: 152158 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00376

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00250 AC: 625 AN: 250424 Hom.: 2 AF XY: 0.00256 AC XY: 347 AN XY: 135570

Gnomad AFR exome AF: 0.000700

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00268

Gnomad FIN exome AF: 0.00365

Gnomad NFE exome AF: 0.00333

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00338 AC: 4935 AN: 1461790 Hom.: 16 Cov.: 30 AF XY: 0.00339 AC XY: 2465 AN XY: 727196

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00228

Gnomad4 FIN exome AF: 0.00363

Gnomad4 NFE exome AF: 0.00379

Gnomad4 OTH exome AF: 0.00308

GnomAD4 genome AF: 0.00249 AC: 379 AN: 152276 Hom.: 3 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74458

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00396

Gnomad4 NFE AF: 0.00376

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00264 Hom.: 0

Bravo AF: 0.00200

EpiCase AF: 0.00300

EpiControl AF: 0.00314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TUBA1A: BP4, BP7, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 07, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.1
DANN	Benign	0.86

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: rs142641191; hg19: chr12-49579183; COSMIC: COSV55497677; COSMIC: COSV55497677;