rs118102196

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006087.4(TUBB4A):c.921C>T(p.His307His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0205 in 1,613,948 control chromosomes in the GnomAD database, including 429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 24 hom., cov: 32)

Exomes 𝑓: 0.021 ( 405 hom. )

Consequence

TUBB4A
NM_006087.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.938

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 19-6495578-G-A is Benign according to our data. Variant chr19-6495578-G-A is described in ClinVar as [Benign]. Clinvar id is 240288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6495578-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.938 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0149 (2272/152338) while in subpopulation NFE AF = 0.0239 (1623/68020). AF 95% confidence interval is 0.0229. There are 24 homozygotes in GnomAd4. There are 998 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2272 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB4A	NM_006087.4 link	c.921C>T	p.His307His	synonymous_variant	Exon 4 of 4	ENST00000264071.7	NP_006078.2	P04350

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB4A	ENST00000264071.7 link	c.921C>T	p.His307His	synonymous_variant	Exon 4 of 4	1	NM_006087.4	ENSP00000264071.1		P04350

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2276

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00429

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0123

Gnomad ASJ

AF:

0.0305

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00620

Gnomad FIN

AF:

0.00659

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0239

Gnomad OTH

AF:

0.0211

GnomAD2 exomes

AF:

0.0164

AC:

4102

AN:

250082

AF XY:

0.0167

show subpopulations

Gnomad AFR exome

AF:

0.00331

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.0289

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00634

Gnomad NFE exome

AF:

0.0250

Gnomad OTH exome

AF:

0.0208

GnomAD4 exome

AF:

0.0211

AC:

30774

AN:

1461610

Hom.:

405

Cov.:

AF XY:

0.0207

AC XY:

15069

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.00353

AC:

118

AN:

33474

American (AMR)

AF:

0.0119

AC:

531

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0288

AC:

752

AN:

26104

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39694

South Asian (SAS)

AF:

0.00864

AC:

745

AN:

86236

European-Finnish (FIN)

AF:

0.00828

AC:

442

AN:

53362

Middle Eastern (MID)

AF:

0.0381

AC:

219

AN:

5754

European-Non Finnish (NFE)

AF:

0.0240

AC:

26722

AN:

1111896

Other (OTH)

AF:

0.0206

AC:

1242

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

2723

5446

8170

10893

13616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0149

AC:

2272

AN:

152338

Hom.:

Cov.:

AF XY:

0.0134

AC XY:

998

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00428

AC:

178

AN:

41584

American (AMR)

AF:

0.0123

AC:

188

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0305

AC:

106

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00600

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00659

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0239

AC:

1623

AN:

68020

Other (OTH)

AF:

0.0208

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

131

261

392

522

653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0219

Hom.:

Bravo

AF:

0.0150

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0256

EpiControl

AF:

0.0289

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypomyelinating leukodystrophy 6

Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:1

May 20, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Torsion dystonia 4

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

TUBB4A-related disorder

Benign:1

Jan 30, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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_noAF

Benign

-0.57

CADD

Benign

9.4

(source)

DANN

Benign

0.60

PhyloP100

0.94

Mutation Taster

=95/5

polymorphism (auto)

(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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rs118102196

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over