rs878853256

Positions:

• chr16-89935418-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_006086.4(TUBB3):​c.967A>G​(p.Met323Val) 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: 𝑓 0.0000066 (0 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: TUBB3 NM_006086.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.22

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBB3. . Gene score misZ 4.5786 (greater than the threshold 3.09). Trascript score misZ 5.665 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.838
• PP5: Variant 16-89935418-A-G is Pathogenic according to our data. Variant chr16-89935418-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 30272.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB3	NM_006086.4	c.967A>G	p.Met323Val	missense_variant	4/4	ENST00000315491.12	NP_006077.2
TUBB3	NM_001197181.2	c.751A>G	p.Met251Val	missense_variant	4/4		NP_001184110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB3	ENST00000315491.12	c.967A>G	p.Met323Val	missense_variant	4/4	1	NM_006086.4	ENSP00000320295.7
ENSG00000198211	ENST00000556922.1	c.2008A>G	p.Met670Val	missense_variant	5/5	2		ENSP00000451560.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 152176 Hom.: 0 Cov.: 33 FAILED QC

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 323 of the TUBB3 protein (p.Met323Val). 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, 33921132; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30272). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects TUBB3 function (PMID: 29382549, 31226147). For these reasons, this variant has been classified as Pathogenic. -

Complex cortical dysplasia with other brain malformations 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 15, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Uncertain	0.63	.;.;D
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.7	.;.;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;.;.
Sift4G	Benign	0.090	T;T;T
Polyphen		0.0010	.;.;B
Vest4		0.86
MutPred		0.48		.;.;Gain of methylation at K324 (P = 0.0301);
MVP		1.0
MPC		1.6
ClinPred		0.94	D
GERP RS		4.6
Varity_R		0.93
gMVP		0.93

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

Other links and lift over

dbSNP: rs878853256; hg19: chr16-90001826;