Genetic Variant TUBB4B:c.-29C>A (chr9-137241332-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_006088.6(TUBB4B):c.-29C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,591,822 control chromosomes in the GnomAD database, including 2,897 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.082 ( 1463 hom., cov: 33)

Exomes 𝑓: 0.013 ( 1434 hom. )

Consequence

TUBB4B
NM_006088.6 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.245

Publications

6 publications found

Variant links:

Genes affected

TUBB4B (HGNC:20771): (tubulin beta 4B class IVb) Enables double-stranded RNA binding activity. Predicted to be involved in microtubule cytoskeleton organization and mitotic cell cycle. Located in microtubule. Implicated in Leber congenital amaurosis with early-onset deafness. [provided by Alliance of Genome Resources, Apr 2022]

TUBB4B Gene-Disease associations (from GenCC):

TUBB4B-related ciliopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Leber congenital amaurosis with early-onset deafness
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

TUBB4B 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 (BayesDel_noAF=-0.71).

BP6

Variant 9-137241332-C-A is Benign according to our data. Variant chr9-137241332-C-A is described in ClinVar as Benign. ClinVar VariationId is 1182505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006088.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB4B	NM_006088.6	MANE Select	c.-29C>A		5_prime_UTR	Exon 1 of 4	NP_006079.1	P68371

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TUBB4B	ENST00000340384.5	TSL:1 MANE Select	c.-29C>A	5_prime_UTR	Exon 1 of 4	ENSP00000341289.4	P68371
TUBB4B	ENST00000604929.1	TSL:1	n.45C>A	non_coding_transcript_exon	Exon 1 of 3
TUBB4B	ENST00000938213.1		c.-29C>A	5_prime_UTR	Exon 1 of 4	ENSP00000608272.1

Frequencies

GnomAD3 genomes

AF:

0.0813

AC:

12333

AN:

151782

Hom.:

1457

Cov.:

show subpopulations

Gnomad AFR

AF:

0.262

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0517

Gnomad ASJ

AF:

0.0142

Gnomad EAS

AF:

0.0404

Gnomad SAS

AF:

0.0257

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.00301

Gnomad OTH

AF:

0.0647

GnomAD2 exomes

AF:

0.0288

AC:

6247

AN:

216792

AF XY:

0.0244

show subpopulations

Gnomad AFR exome

AF:

0.276

Gnomad AMR exome

AF:

0.0397

Gnomad ASJ exome

AF:

0.0164

Gnomad EAS exome

AF:

0.0330

Gnomad FIN exome

AF:

0.000473

Gnomad NFE exome

AF:

0.00297

Gnomad OTH exome

AF:

0.0201

GnomAD4 exome

AF:

0.0128

AC:

18423

AN:

1439924

Hom.:

1434

Cov.:

AF XY:

0.0122

AC XY:

8747

AN XY:

716436

show subpopulations

African (AFR)

AF:

0.270

AC:

8749

AN:

32408

American (AMR)

AF:

0.0423

AC:

1863

AN:

44092

Ashkenazi Jewish (ASJ)

AF:

0.0158

AC:

409

AN:

25876

East Asian (EAS)

AF:

0.0383

AC:

1476

AN:

38538

South Asian (SAS)

AF:

0.0200

AC:

1705

AN:

85332

European-Finnish (FIN)

AF:

0.000485

AC:

AN:

41230

Middle Eastern (MID)

AF:

0.0389

AC:

223

AN:

5740

European-Non Finnish (NFE)

AF:

0.00210

AC:

2327

AN:

1106952

Other (OTH)

AF:

0.0276

AC:

1651

AN:

59756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

753

1507

2260

3014

3767

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

360

720

1080

1440

1800

<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:

0.0815

AC:

12380

AN:

151898

Hom.:

1463

Cov.:

AF XY:

0.0788

AC XY:

5856

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.262

AC:

10839

AN:

41426

American (AMR)

AF:

0.0520

AC:

794

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0142

AC:

AN:

3454

East Asian (EAS)

AF:

0.0407

AC:

210

AN:

5156

South Asian (SAS)

AF:

0.0257

AC:

124

AN:

4816

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00299

AC:

203

AN:

67856

Other (OTH)

AF:

0.0692

AC:

146

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

472

945

1417

1890

2362

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

240

360

480

600

<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.:

Bravo

AF:

0.0927

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

3.8

(source)

DANN

Benign

0.41

PhyloP100

0.24

PromoterAI

-0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=300/0

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