16-89935355-G-T

Variant names:

• chr16-89935355-G-T
• rs267607163
• NM_006086.4:c.904G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_006086.4(TUBB3):​c.904G>T​(p.Ala302Ser) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A302V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TUBB3 NM_006086.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.89
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex cortical dysplasia with other brain malformations 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Illumina
• fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• congenital fibrosis of extraocular muscles

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tubulinopathy-associated dysgyria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000198211 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 4 uncertain in NM_006086.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-89935356-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30275.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement, tubulinopathy-associated dysgyria, congenital fibrosis of extraocular muscles, complex cortical dysplasia with other brain malformations 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 16-89935355-G-T is Pathogenic according to our data. Variant chr16-89935355-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2744601.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB3	NM_006086.4	c.904G>T	p.Ala302Ser	missense_variant	Exon 4 of 4	ENST00000315491.12	NP_006077.2
TUBB3	NM_001197181.2	c.688G>T	p.Ala230Ser	missense_variant	Exon 4 of 4		NP_001184110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB3	ENST00000315491.12	c.904G>T	p.Ala302Ser	missense_variant	Exon 4 of 4	1	NM_006086.4	ENSP00000320295.7
ENSG00000198211	ENST00000556922.1	c.1945G>T	p.Ala649Ser	missense_variant	Exon 5 of 5	2		ENSP00000451560.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Sep 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 302 of the TUBB3 protein (p.Ala302Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features consistent with cortical dysplasia (Invitae). In at least one individual the variant was observed to be de novo. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TUBB3 protein function. This variant disrupts the p.Ala302 amino acid residue in TUBB3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20074521, 29382549, 31226147). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;.;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	0.0	.;.;M
PhyloP100		9.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.031	D;D;T
Vest4		0.55
ClinPred		0.96	D
GERP RS		4.6
Varity_R		0.86
gMVP		0.89

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

Other links and lift over

dbSNP: rs267607163; hg19: chr16-90001763;