rs140943896

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_030773.4(TUBB1):c.1075C>T(p.Arg359Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0049 in 1,614,162 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R359Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0054 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 47 hom. )

Consequence

TUBB1
NM_030773.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 5.01

Publications

12 publications found

Variant links:

Genes affected

TUBB1 (HGNC:16257): (tubulin beta 1 class VI) This gene encodes a member of the beta tubulin protein family. Beta tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. This protein is specifically expressed in platelets and megakaryocytes and may be involved in proplatelet production and platelet release. A mutations in this gene is associated with autosomal dominant macrothrombocytopenia. Two pseudogenes of this gene are found on chromosome Y.[provided by RefSeq, Jul 2010]

TUBB1 Gene-Disease associations (from GenCC):

macrothrombocytopenia, isolated, 1, autosomal dominant
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, ClinGen
autosomal dominant macrothrombocytopenia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TUBB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012478262).

BP6

Variant 20-59024502-C-T is Benign according to our data. Variant chr20-59024502-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 377103.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00544 (828/152274) while in subpopulation NFE AF = 0.00473 (322/68030). AF 95% confidence interval is 0.00431. There are 10 homozygotes in GnomAd4. There are 503 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 828 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB1	NM_030773.4 link	c.1075C>T	p.Arg359Trp	missense_variant	Exon 4 of 4	ENST00000217133.2	NP_110400.1	Q9H4B7
TUBB1	XM_017028085.2 link	c.1009C>T	p.Arg337Trp	missense_variant	Exon 4 of 4		XP_016883574.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB1	ENST00000217133.2 link	c.1075C>T	p.Arg359Trp	missense_variant	Exon 4 of 4	1	NM_030773.4	ENSP00000217133.1		Q9H4B7

Frequencies

GnomAD3 genomes

AF:

0.00544

AC:

828

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0416

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00473

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00658

AC:

1655

AN:

251418

AF XY:

0.00646

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0401

Gnomad NFE exome

AF:

0.00573

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00484

AC:

7081

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00480

AC XY:

3494

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33480

American (AMR)

AF:

0.00148

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000962

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0406

AC:

2169

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00404

AC:

4497

AN:

1112008

Other (OTH)

AF:

0.00416

AC:

251

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

539

1078

1616

2155

2694

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

288

432

576

720

<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:

0.00544

AC:

828

AN:

152274

Hom.:

Cov.:

AF XY:

0.00675

AC XY:

503

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000626

AC:

AN:

41554

American (AMR)

AF:

0.00163

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00125

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0416

AC:

441

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00473

AC:

322

AN:

68030

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

127

169

211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00324

Hom.:

Bravo

AF:

0.00250

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.00623

AC:

756

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00431

EpiControl

AF:

0.00433

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TUBB1: BS1, BS2 -

Feb 01, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1, BS2 -

Jan 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Macrothrombocytopenia, isolated, 1, autosomal dominant

Uncertain:1

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Apr 05, 2019

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TUBB1-related disorder

Benign:1

Apr 30, 2019

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

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.012

MetaSVM

Uncertain

0.099

MutationAssessor

Pathogenic

3.0

PhyloP100

5.0

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

Sift4G

Benign

0.065

Polyphen

1.0

Vest4

0.45

MVP

0.93

MPC

0.55

ClinPred

0.034

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.57

gMVP

0.62

Mutation Taster

=92/8

polymorphism

(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