16-89923410-G-C

Variant names:

• chr16-89923410-G-C
• NM_006086.4:c.9G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_006086.4(TUBB3):​c.9G>C​(p.Glu3Asp) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TUBB3 NM_006086.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.521

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]

ENSG00000198211 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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, 0.939

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB3	NM_006086.4	c.9G>C	p.Glu3Asp	missense_variant	Exon 1 of 4	ENST00000315491.12	NP_006077.2
TUBB3	NM_001197181.2	c.-160+1165G>C		intron_variant	Intron 1 of 3		NP_001184110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB3	ENST00000315491.12	c.9G>C	p.Glu3Asp	missense_variant	Exon 1 of 4	1	NM_006086.4	ENSP00000320295.7
ENSG00000198211	ENST00000556922.1	c.1098+2673G>C		intron_variant	Intron 2 of 4	2		ENSP00000451560.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 17, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;D;T;.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	4.4	.;H;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.80	.;N;N;N;N
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	.;.;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.80
MutPred		0.78		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.98
MPC		2.6
ClinPred		0.98	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.80
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-89989818; COSMIC: COSV105131299; COSMIC: COSV105131299;