rs878853257

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong

The NM_006086.4(TUBB3):c.613G>A(p.Glu205Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

TUBB3
NM_006086.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 9.91

Variant links:

Genes affected

TUBB3 (HGNC:20772): (tubulin beta 3 class III) This gene encodes a class III 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 primarily expressed in neurons and may be involved in neurogenesis and axon guidance and maintenance. Mutations in this gene are the cause of congenital fibrosis of the extraocular muscles type 3. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 6. [provided by RefSeq, Oct 2010]

TUBB3 links:

ENSG00000198211 (HGNC:):

ENSG00000198211 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the TUBB3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 4.5786 (above the threshold of 3.09). Trascript score misZ: 5.665 (above the threshold of 3.09). GenCC associations: The gene is linked to tubulinopathy-associated dysgyria, complex cortical dysplasia with other brain malformations 1, congenital fibrosis of extraocular muscles, fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.918

PP5

Variant 16-89935064-G-A is Pathogenic according to our data. Variant chr16-89935064-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB3	NM_006086.4 link	c.613G>A	p.Glu205Lys	missense_variant	Exon 4 of 4	ENST00000315491.12	NP_006077.2	Q13509-1Q53G92
TUBB3	NM_001197181.2 link	c.397G>A	p.Glu133Lys	missense_variant	Exon 4 of 4		NP_001184110.1	Q13509-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB3	ENST00000315491.12 link	c.613G>A	p.Glu205Lys	missense_variant	Exon 4 of 4	1	NM_006086.4	ENSP00000320295.7		Q13509-1
ENSG00000198211	ENST00000556922.1 link	c.1654G>A	p.Glu552Lys	missense_variant	Exon 5 of 5	2		ENSP00000451560.1		A0A0B4J269

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Dec 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: impaired ability to form heterodimers (Poirier et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 24860126, 26130693, 26934450, 37600020, 31226147, 32573066, 29382549, 32169460, 20829227, 26639658, 22591407) -

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 205 of the TUBB3 protein (p.Glu205Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TUBB3-related conditions (PMID: 20829227). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30274). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TUBB3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TUBB3 function (PMID: 20829227). For these reasons, this variant has been classified as Pathogenic. -

Complex cortical dysplasia with other brain malformations 1

Pathogenic:3

Jul 25, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM2, PM5, PP2, PP3, PP5 -

Nov 15, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 04, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

.;.;.;D

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Uncertain

0.36

MutationAssessor

Pathogenic

3.8

.;.;.;H

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0020

D;.;.;.

Sift4G

Uncertain

0.011

D;D;D;D

Polyphen

0.98

.;.;.;D

Vest4

0.94

MutPred

0.78

.;.;.;Gain of methylation at E205 (P = 0.0158);

MVP

0.97

MPC

2.6

ClinPred

0.99

GERP RS

4.8

Varity_R

0.97

gMVP

0.99

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