Genetic Variant TUBB4A:p.Thr429Thr (chr19-6495212-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001289123.2(TUBB4A):c.1440G>A(p.Thr480Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,613,922 control chromosomes in the GnomAD database, including 437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T480T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.017 ( 31 hom., cov: 32)

Exomes 𝑓: 0.022 ( 406 hom. )

Consequence

TUBB4A
NM_001289123.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -5.13

Publications

6 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:

ENSG00000268191 (HGNC:):

ENSG00000268191 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 19-6495212-C-T is Benign according to our data. Variant chr19-6495212-C-T is described in ClinVar as Benign. ClinVar VariationId is 330260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.13 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.017 (2584/152240) while in subpopulation NFE AF = 0.0251 (1706/67986). AF 95% confidence interval is 0.0241. There are 31 homozygotes in GnomAd4. There are 1221 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2584 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001289123.2. 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.1287G>A	p.Thr429Thr	synonymous	Exon 4 of 4	NP_006078.2
TUBB4A	NM_001289123.2		c.1440G>A	p.Thr480Thr	synonymous	Exon 5 of 5	NP_001276052.1
TUBB4A	NM_001289127.2		c.1422G>A	p.Thr474Thr	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.1287G>A	p.Thr429Thr	synonymous	Exon 4 of 4	ENSP00000264071.1
TUBB4A	ENST00000598635.2	TSL:4	c.1440G>A	p.Thr480Thr	synonymous	Exon 5 of 5	ENSP00000470627.2
TUBB4A	ENST00000597686.6	TSL:4	c.1422G>A	p.Thr474Thr	synonymous	Exon 5 of 5	ENSP00000472375.2

Frequencies

GnomAD3 genomes

AF:

0.0170

AC:

2584

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00463

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0189

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0295

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0251

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.0179

AC:

4500

AN:

251232

AF XY:

0.0175

show subpopulations

Gnomad AFR exome

AF:

0.00462

Gnomad AMR exome

AF:

0.0147

Gnomad ASJ exome

AF:

0.00843

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0346

Gnomad NFE exome

AF:

0.0249

Gnomad OTH exome

AF:

0.0240

GnomAD4 exome

AF:

0.0224

AC:

32797

AN:

1461682

Hom.:

406

Cov.:

AF XY:

0.0220

AC XY:

15997

AN XY:

727150

show subpopulations

African (AFR)

AF:

0.00400

AC:

134

AN:

33472

American (AMR)

AF:

0.0150

AC:

672

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00918

AC:

240

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00413

AC:

356

AN:

86252

European-Finnish (FIN)

AF:

0.0369

AC:

1972

AN:

53420

Middle Eastern (MID)

AF:

0.00383

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0253

AC:

28144

AN:

1111870

Other (OTH)

AF:

0.0208

AC:

1256

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

2404

4808

7212

9616

12020

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

986

1972

2958

3944

4930

<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:

0.0170

AC:

2584

AN:

152240

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1221

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00465

AC:

193

AN:

41548

American (AMR)

AF:

0.0189

AC:

289

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00806

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00290

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0295

AC:

313

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0251

AC:

1706

AN:

67986

Other (OTH)

AF:

0.0180

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

126

252

377

503

629

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:

0.0180

Hom.:

Bravo

AF:

0.0161

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0225

EpiControl

AF:

0.0238

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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.36

(source)

DANN

Benign

0.85

PhyloP100

-5.1

Mutation Taster

=98/2

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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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

Computational scores

Splicing

Publications

Other links and lift over