Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The ENST00000550767.6(TUBA1A):c.-101G>A variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Consequence

TUBA1A
ENST00000550767.6 5_prime_UTR_premature_start_codon_gain

Scores

Splicing: ADA: 0.9802

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 6.09

Publications

14 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 12-49186832-C-T is Pathogenic according to our data. Variant chr12-49186832-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 160161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000550767.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TUBA1A	NM_006009.4	MANE Select	c.5G>A	p.Arg2His	missense splice_region	Exon 2 of 4	NP_006000.2
TUBA1A	NM_001270400.2		c.-101G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	NP_001257329.1
TUBA1A	NM_001270399.2		c.5G>A	p.Arg2His	missense splice_region	Exon 2 of 4	NP_001257328.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TUBA1A	ENST00000550767.6	TSL:1	c.-101G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 5	ENSP00000446637.1
TUBA1A	ENST00000301071.12	TSL:1 MANE Select	c.5G>A	p.Arg2His	missense splice_region	Exon 2 of 4	ENSP00000301071.7
TUBA1A	ENST00000550767.6	TSL:1	c.-101G>A		splice_region	Exon 3 of 5	ENSP00000446637.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000108

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lissencephaly due to TUBA1A mutation (4)

not provided (2)

Inborn genetic diseases (1)

Neurodevelopmental disorder (1)

Seizure;C0424688:Decreased head circumference;C0557874:Global developmental delay (1)

TUBA1A-related disorder (1)

Tubulinopathy (1)

Tubulinopathy-associated dysgyria (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.076

MetaRNN

Uncertain

0.50

MetaSVM

Uncertain

-0.066

MutationAssessor

Pathogenic

3.1

PhyloP100

6.1

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.62

Sift

Uncertain

0.0090

Sift4G

Benign

0.081

Polyphen

0.81

Vest4

0.42

MutPred

0.58

Gain of catalytic residue at S6 (P = 9e-04)

MVP

0.87

MPC

4.2

ClinPred

0.99

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.43

gMVP

0.97

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.79

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

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ENST00000550767.6:c.-101G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over