rs150812047

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006087.4(TUBB4A):c.189G>A(p.Ala63=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00319 in 1,613,854 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A63A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 11 hom. )

Consequence

TUBB4A
NM_006087.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.557

Variant links:

Genes affected

TUBB4A (HGNC:20774): (tubulin beta 4A class IVa) This gene encodes a member of the beta tubulin family. Beta tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. Mutations in this gene cause hypomyelinating leukodystrophy-6 and autosomal dominant torsion dystonia-4. Alternate splicing results in multiple transcript variants encoding different isoforms. A pseudogene of this gene is found on chromosome X. [provided by RefSeq, Jan 2014]

TUBB4A links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004796207).

BP6

Variant 19-6501375-C-T is Benign according to our data. Variant chr19-6501375-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 330267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6501375-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.557 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00248 (378/152314) while in subpopulation NFE AF= 0.00447 (304/68016). AF 95% confidence interval is 0.00406. There are 0 homozygotes in gnomad4. There are 188 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 378 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB4A	NM_006087.4 linkuse as main transcript	c.189G>A	p.Ala63=	synonymous_variant	3/4	ENST00000264071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB4A	ENST00000264071.7 linkuse as main transcript	c.189G>A	p.Ala63=	synonymous_variant	3/4	1	NM_006087.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

378

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00447

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00215

AC:

540

AN:

250720

Hom.:

AF XY:

0.00224

AC XY:

303

AN XY:

135500

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00154

Gnomad ASJ exome

AF:

0.000995

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00134

Gnomad FIN exome

AF:

0.000232

Gnomad NFE exome

AF:

0.00366

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00326

AC:

4763

AN:

1461540

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

2390

AN XY:

727032

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.00181

Gnomad4 ASJ exome

AF:

0.000919

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00155

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.00391

Gnomad4 OTH exome

AF:

0.00245

GnomAD4 genome

AF:

0.00248

AC:

378

AN:

152314

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

188

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00447

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00369

Hom.:

Bravo

AF:

0.00221

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00226

AC:

274

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00409

EpiControl

AF:

0.00403

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypomyelinating leukodystrophy 6

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2019	This variant is associated with the following publications: (PMID: 26318963) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TUBB4A: BP4, BP7 -

Torsion dystonia 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

TUBB4A-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 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

Benign

-0.45

BayesDel_noAF

Benign

-0.41

Cadd

Benign

2.2

Dann

Benign

0.93

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.36

T;T

M_CAP

Benign

0.0060

MetaRNN

Benign

0.0048

T;T

MutationTaster

Benign

1.0

D;D

Sift4G

Benign

0.40

T;T

Vest4

0.22

MVP

0.42

GERP RS

-7.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over