Genetic Variant NM_006082.3:c.519A>G (chr12-49128795-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006082.3(TUBA1B):c.519A>G(p.Pro173Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 1,487,486 control chromosomes in the GnomAD database, including 123,890 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 16481 hom., cov: 28)

Exomes 𝑓: 0.36 ( 107409 hom. )

Consequence

TUBA1B
NM_006082.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.21

Publications

11 publications found

Variant links:

Genes affected

TUBA1B (HGNC:18809): (tubulin alpha 1b) Enables double-stranded RNA binding activity and ubiquitin protein ligase binding activity. Predicted to be involved in microtubule cytoskeleton organization and mitotic cell cycle. Predicted to act upstream of or within cellular response to interleukin-4. Located in microtubule. [provided by Alliance of Genome Resources, Apr 2022]

TUBA1B links:

TUBA1B-AS1 (HGNC:56356): (TUBA1B antisense RNA 1)

TUBA1B-AS1 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=-0.64).

BP6

Variant 12-49128795-T-C is Benign according to our data. Variant chr12-49128795-T-C is described in ClinVar as Benign. ClinVar VariationId is 768541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.2 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA1B	NM_006082.3 link	c.519A>G	p.Pro173Pro	synonymous_variant	Exon 4 of 4	ENST00000336023.9	NP_006073.2	P68363-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA1B	ENST00000336023.9 link	c.519A>G	p.Pro173Pro	synonymous_variant	Exon 4 of 4	1	NM_006082.3	ENSP00000336799.5		P68363-1

Frequencies

GnomAD3 genomes

AF:

0.445

AC:

67015

AN:

150740

Hom.:

16438

Cov.:

show subpopulations

Gnomad AFR

AF:

0.640

Gnomad AMI

AF:

0.220

Gnomad AMR

AF:

0.365

Gnomad ASJ

AF:

0.270

Gnomad EAS

AF:

0.713

Gnomad SAS

AF:

0.556

Gnomad FIN

AF:

0.384

Gnomad MID

AF:

0.263

Gnomad NFE

AF:

0.340

Gnomad OTH

AF:

0.411

GnomAD2 exomes

AF:

0.365

AC:

71414

AN:

195902

AF XY:

0.364

show subpopulations

Gnomad AFR exome

AF:

0.634

Gnomad AMR exome

AF:

0.294

Gnomad ASJ exome

AF:

0.200

Gnomad EAS exome

AF:

0.757

Gnomad FIN exome

AF:

0.346

Gnomad NFE exome

AF:

0.258

Gnomad OTH exome

AF:

0.327

GnomAD4 exome

AF:

0.361

AC:

482330

AN:

1336628

Hom.:

107409

Cov.:

AF XY:

0.364

AC XY:

242104

AN XY:

665034

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.660

AC:

20792

AN:

31512

American (AMR)

AF:

0.329

AC:

13094

AN:

39814

Ashkenazi Jewish (ASJ)

AF:

0.261

AC:

6390

AN:

24470

East Asian (EAS)

AF:

0.721

AC:

27335

AN:

37926

South Asian (SAS)

AF:

0.530

AC:

41520

AN:

78306

European-Finnish (FIN)

AF:

0.378

AC:

19383

AN:

51280

Middle Eastern (MID)

AF:

0.262

AC:

1447

AN:

5522

European-Non Finnish (NFE)

AF:

0.327

AC:

331134

AN:

1011826

Other (OTH)

AF:

0.379

AC:

21235

AN:

55972

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.331

Heterozygous variant carriers

19189

38378

57566

76755

95944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10188

20376

30564

40752

50940

<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:

0.445

AC:

67117

AN:

150858

Hom.:

16481

Cov.:

AF XY:

0.448

AC XY:

33013

AN XY:

73648

show subpopulations

African (AFR)

AF:

0.640

AC:

26200

AN:

40922

American (AMR)

AF:

0.365

AC:

5537

AN:

15152

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

934

AN:

3462

East Asian (EAS)

AF:

0.714

AC:

3658

AN:

5126

South Asian (SAS)

AF:

0.555

AC:

2630

AN:

4738

European-Finnish (FIN)

AF:

0.384

AC:

4004

AN:

10430

Middle Eastern (MID)

AF:

0.259

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.340

AC:

23022

AN:

67740

Other (OTH)

AF:

0.410

AC:

856

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

1525

3050

4574

6099

7624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

614

1228

1842

2456

3070

<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:

0.359

Hom.:

1889

Bravo

AF:

0.449

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 27, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.1

(source)

DANN

Benign

0.56

PhyloP100

-2.2

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.8

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over