rs140943896

Positions:

chr20-59024502-C-T

Variant summary

Our verdict is Benign. Variant got -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).

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:1B:5

Conservation

PhyloP100: 5.01

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 377103.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=3, Uncertain_significance=2}.

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 828 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB1	NM_030773.4 linkuse as main transcript	c.1075C>T	p.Arg359Trp	missense_variant	4/4	ENST00000217133.2	NP_110400.1
TUBB1	XM_017028085.2 linkuse as main transcript	c.1009C>T	p.Arg337Trp	missense_variant	4/4		XP_016883574.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB1	ENST00000217133.2 linkuse as main transcript	c.1075C>T	p.Arg359Trp	missense_variant	4/4	1	NM_030773.4	ENSP00000217133	P1

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

GnomAD3 exomes

AF:

0.00658

AC:

1655

AN:

251418

Hom.:

AF XY:

0.00646

AC XY:

878

AN XY:

135898

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 SAS exome

AF:

0.000980

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

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000962

Gnomad4 FIN exome

AF:

0.0406

Gnomad4 NFE exome

AF:

0.00404

Gnomad4 OTH exome

AF:

0.00416

GnomAD4 genome

AF:

0.00544

AC:

828

AN:

152274

Hom.:

Cov.:

AF XY:

0.00675

AC XY:

503

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.0416

Gnomad4 NFE

AF:

0.00473

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00381

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:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	TUBB1: BS1, BS2 -

Macrothrombocytopenia, isolated, 1, autosomal dominant

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 05, 2019

- -

TUBB1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2019

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

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

MutationTaster

Benign

1.0

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over