rs878853258

Variant names:

• chr16-89935356-C-T
• rs878853258
• NM_006086.4:c.905C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_006086.4(TUBB3):​c.905C>T​(p.Ala302Val) 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A302T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TUBB3 NM_006086.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.82
• Publications: 10 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 12 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 chr16-89935355-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.961
• PP5: Variant 16-89935356-C-T is Pathogenic according to our data. 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006086.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB3	NM_006086.4	MANE Select	c.905C>T	p.Ala302Val	missense	Exon 4 of 4	NP_006077.2
	TUBB3	NM_001197181.2		c.689C>T	p.Ala230Val	missense	Exon 4 of 4	NP_001184110.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB3	ENST00000315491.12	TSL:1 MANE Select	c.905C>T	p.Ala302Val	missense	Exon 4 of 4	ENSP00000320295.7
	ENSG00000198211	ENST00000556922.1	TSL:2	c.1946C>T	p.Ala649Val	missense	Exon 5 of 5	ENSP00000451560.1
	TUBB3	ENST00000554444.5	TSL:2	c.689C>T	p.Ala230Val	missense	Exon 4 of 4	ENSP00000451617.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Complex cortical dysplasia with other brain malformations 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.88
MutPred		0.77		Loss of ubiquitination at K297 (P = 0.0727)
MVP		0.97
MPC		2.6
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.87
gMVP		0.95
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs878853258; hg19: chr16-90001764;