chr20-59019535-G-A

Position:

chr20-59019535-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_030773.4(TUBB1):c.13G>A(p.Val5Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000216 in 1,614,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

TUBB1
NM_030773.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 9.89

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=0.011953056).

BP6

Variant 20-59019535-G-A is Benign according to our data. Variant chr20-59019535-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 988861.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00121 (184/152302) while in subpopulation AFR AF= 0.00395 (164/41558). AF 95% confidence interval is 0.00345. There are 0 homozygotes in gnomad4. There are 83 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 184 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB1	NM_030773.4 linkuse as main transcript	c.13G>A	p.Val5Ile	missense_variant	1/4	ENST00000217133.2	NP_110400.1	Q9H4B7
TUBB1	XM_017028085.2 linkuse as main transcript	c.-10+2990G>A		intron_variant			XP_016883574.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB1	ENST00000217133.2 linkuse as main transcript	c.13G>A	p.Val5Ile	missense_variant	1/4	1	NM_030773.4	ENSP00000217133.1		Q9H4B7

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

183

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00393

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000274

AC:

AN:

251400

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000112

AC:

164

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000935

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00415

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.00121

AC:

184

AN:

152302

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00395

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000248

Hom.:

Bravo

AF:

0.00126

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000321

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 16, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 08, 2024	BS1, PM1 -

Macrothrombocytopenia, isolated, 1, autosomal dominant

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

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

- -

Thrombocytopenia;C1458140:Abnormal bleeding

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Birmingham Platelet Group; University of Birmingham

May 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.061

Eigen

Benign

-0.099

Eigen_PC

Benign

0.038

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.030

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.18

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.15

REVEL

Benign

0.26

Sift

Uncertain

0.0010

Sift4G

Benign

0.49

Polyphen

0.17

Vest4

0.52

MVP

0.36

MPC

0.66

ClinPred

0.085

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.28

gMVP

0.24

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