chr16-89935679-G-A

Variant names:

• chr16-89935679-G-A
• rs267607165
• NM_006086.4:c.1228G>A

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_006086.4(TUBB3):​c.1228G>A​(p.Glu410Lys) 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 (★★). ClinVar reports functional evidence for this variant: "SCV001445868: Functional studies have shown that the c.1228G>A (p.Glu410Lys) variant inhibits axonal transport of vesicles and mitochondria (PMID:23503589). This variant is in the H12 helix of beta-tubulin and changes the negative charge on the surface of the microtubule, which is important for binding to kinesin superfamily motor proteins (KIFs). The disrupted binding of axonal transport KIFs to microtubules alters the localization of KIFs in neurons and inhibits axon elongation (PMID:23503589)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TUBB3 NM_006086.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 9.92
• Publications: 53 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):

• TUBB3-related tubulinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• complex cortical dysplasia with other brain malformations 1

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

  Inheritance: AD Classification: STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001445868: Functional studies have shown that the c.1228G>A (p.Glu410Lys) variant inhibits axonal transport of vesicles and mitochondria (PMID: 23503589). This variant is in the H12 helix of beta-tubulin and changes the negative charge on the surface of the microtubule, which is important for binding to kinesin superfamily motor proteins (KIFs). The disrupted binding of axonal transport KIFs to microtubules alters the localization of KIFs in neurons and inhibits axon elongation (PMID: 23503589).; SCV001757316: Published functional studies demonstrate E410K affected microtubule polymerization and depolymerization rates as well as kinesin interactions on microtubules and reduced axonal transport of mitochondria in peripheral neurons independent of tubulin isoform (Tischfield et al., 2010; Niwa et al., 2013); SCV004104041: "In vitro functional studies indicate that the p.Glu410Lys change significantly inhibits axonal transport of vesicles and mitochondria." PMID:23503589
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_006086.4
• 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 fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement, complex cortical dysplasia with other brain malformations 1, tubulinopathy-associated dysgyria, congenital fibrosis of extraocular muscles, TUBB3-related tubulinopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 16-89935679-G-A is Pathogenic according to our data. Variant chr16-89935679-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB3	NM_006086.4	MANE Select	c.1228G>A	p.Glu410Lys	missense	Exon 4 of 4	NP_006077.2	Q13509-1
	TUBB3	NM_001197181.2		c.1012G>A	p.Glu338Lys	missense	Exon 4 of 4	NP_001184110.1	Q13509-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB3	ENST00000315491.12	TSL:1 MANE Select	c.1228G>A	p.Glu410Lys	missense	Exon 4 of 4	ENSP00000320295.7	Q13509-1
	ENSG00000198211	ENST00000556922.1	TSL:2	c.2269G>A	p.Glu757Lys	missense	Exon 5 of 5	ENSP00000451560.1	A0A0B4J269
	TUBB3	ENST00000554444.5	TSL:2	c.1012G>A	p.Glu338Lys	missense	Exon 4 of 4	ENSP00000451617.1	Q13509-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Complex cortical dysplasia with other brain malformations 1 (2)
2	-	-	Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement (3)
2	-	-	not provided (2)
1	-	-	TUBB3-related disorder (1)
1	-	-	TUBB3-Releated Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.91	P
Vest4		0.90
MutPred		0.80		Gain of ubiquitination at E410 (P = 0.009)
MVP		1.0
MPC		1.7
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.56
gMVP		0.99
Mutation Taster		=2/98	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: rs267607165; hg19: chr16-90002087; COSMIC: COSV100206073; COSMIC: COSV100206073;