12-49186412-T-C

Position:

• chr12-49186412-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_006009.4(TUBA1A):​c.273A>G​(p.Gln91=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TUBA1A NM_006009.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.21

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 Likely_benign. Variant got -1 ACMG points.

• BP6: Variant 12-49186412-T-C is Benign according to our data. Variant chr12-49186412-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212492.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr12-49186412-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBA1A	NM_006009.4	c.273A>G	p.Gln91=	synonymous_variant	3/4	ENST00000301071.12	NP_006000.2
TUBA1A	NM_001270399.2	c.273A>G	p.Gln91=	synonymous_variant	3/4		NP_001257328.1
TUBA1A	NM_001270400.2	c.168A>G	p.Gln56=	synonymous_variant	3/4		NP_001257329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12	c.273A>G	p.Gln91=	synonymous_variant	3/4	1	NM_006009.4	ENSP00000301071	P1
TUBA1B-AS1	ENST00000656133.1	n.474-1871T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 85 AN: 149280 Hom.: 0 Cov.: 30 FAILED QC

Gnomad AFR AF: 0.000171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000678

Gnomad ASJ AF: 0.000593

Gnomad EAS AF: 0.000795

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00270

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000447

Gnomad OTH AF: 0.00196

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000234 AC: 34 AN: 1450206 Hom.: 0 Cov.: 46 AF XY: 0.0000236 AC XY: 17 AN XY: 721540

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000105

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.000157

Gnomad4 NFE exome AF: 0.00000903

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000569 AC: 85 AN: 149378 Hom.: 0 Cov.: 30 AF XY: 0.000741 AC XY: 54 AN XY: 72884

Gnomad4 AFR AF: 0.000170

Gnomad4 AMR AF: 0.000678

Gnomad4 ASJ AF: 0.000593

Gnomad4 EAS AF: 0.000797

Gnomad4 SAS AF: 0.000210

Gnomad4 FIN AF: 0.00270

Gnomad4 NFE AF: 0.000447

Gnomad4 OTH AF: 0.00194

Alfa AF: 0.00158 Hom.: 0

ExAC AF: 0.000898 AC: 109

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 08, 2022	This sequence change affects codon 91 of the TUBA1A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TUBA1A protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TUBA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 212492). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 28, 2015

- -

TUBA1A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2019

This variant is classified as likely 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	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	15
DANN	Benign	0.73
Eigen	Benign	0.016
Eigen_PC	Benign	0.062
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;N
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.80	T
Vest4		0.20
MVP		0.63
ClinPred		0.17	T
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs765483435; hg19: chr12-49580195; COSMIC: COSV105889674; COSMIC: COSV105889674;