12-49186496-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006009.4(TUBA1A):c.227-38C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 151,590 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 58 hom., cov: 31)

Exomes 𝑓: 0.0021 ( 65 hom. )

Failed GnomAD Quality Control

Consequence

TUBA1A
NM_006009.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0450

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029357076).

BP6

Variant 12-49186496-G-C is Benign according to our data. Variant chr12-49186496-G-C is described in ClinVar as Benign. ClinVar VariationId is 259900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
TUBA1A	NM_006009.4 link	c.227-38C>G	intron_variant	Intron 2 of 3	ENST00000301071.12	NP_006000.2
TUBA1A	NM_001270399.2 link	c.227-38C>G	intron_variant	Intron 2 of 3		NP_001257328.1
TUBA1A	NM_001270400.2 link	c.122-38C>G	intron_variant	Intron 2 of 3		NP_001257329.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA1A	ENST00000301071.12 link	c.227-38C>G		intron_variant	Intron 2 of 3	1	NM_006009.4	ENSP00000301071.7

Frequencies

GnomAD3 genomes

AF:

0.0190

AC:

2885

AN:

151474

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0664

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00782

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000624

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.00535

AC:

1343

AN:

251068

AF XY:

0.00389

show subpopulations

Gnomad AFR exome

AF:

0.0710

Gnomad AMR exome

AF:

0.00443

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000881

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00210

AC:

3070

AN:

1460286

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

1327

AN XY:

726198

show subpopulations

African (AFR)

AF:

0.0727

AC:

2420

AN:

33290

American (AMR)

AF:

0.00459

AC:

205

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.000464

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00352

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.0000648

AC:

AN:

1110914

Other (OTH)

AF:

0.00513

AC:

309

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

130

259

389

518

648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0191

AC:

2902

AN:

151590

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

1323

AN XY:

74106

show subpopulations

African (AFR)

AF:

0.0667

AC:

2738

AN:

41066

American (AMR)

AF:

0.00781

AC:

119

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.000624

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67958

Other (OTH)

AF:

0.0133

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

108

215

323

430

538

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0114

Hom.:

ESP6500AA

AF:

0.0606

AC:

267

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00647

AC:

786

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 13, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.64

(source)

DANN

Benign

0.58

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.19

MetaRNN

Benign

0.0029

MetaSVM

Benign

-0.89

PhyloP100

-0.045

PROVEAN

Benign

-0.76

REVEL

Benign

0.066

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Vest4

0.26

ClinPred

0.0047

GERP RS

-4.3

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over