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

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

hypomyelinating leukodystrophy 6
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Illumina
TUBB4A-related neurologic disorder
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
torsion dystonia 4
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

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 VariationId is 240288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006087.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TUBB4A	NM_006087.4	MANE Select	c.921C>T	p.His307His	synonymous	Exon 4 of 4	NP_006078.2
TUBB4A	NM_001289123.2		c.1074C>T	p.His358His	synonymous	Exon 5 of 5	NP_001276052.1
TUBB4A	NM_001289127.2		c.1056C>T	p.His352His	synonymous	Exon 5 of 5	NP_001276056.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TUBB4A	ENST00000264071.7	TSL:1 MANE Select	c.921C>T	p.His307His	synonymous	Exon 4 of 4	ENSP00000264071.1
TUBB4A	ENST00000598635.2	TSL:4	c.1074C>T	p.His358His	synonymous	Exon 5 of 5	ENSP00000470627.2
TUBB4A	ENST00000597686.6	TSL:4	c.1056C>T	p.His352His	synonymous	Exon 5 of 5	ENSP00000472375.2

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

Age Distribution

Exome Het

Exome Hom

Variant carriers

976

1952

2928

3904

4880

<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:

0.0149

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

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0219

Hom.:

Bravo

AF:

0.0150

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0256

EpiControl

AF:

0.0289

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypomyelinating leukodystrophy 6 (2)

not provided (1)

not specified (1)

Torsion dystonia 4 (1)

TUBB4A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over