rs2302898

Variant names:

• chr16-89932386-G-A
• rs2302898
• NM_006086.4:c.58-185G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006086.4(TUBB3):​c.58-185G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 152,052 control chromosomes in the GnomAD database, including 8,784 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.33 (8784 hom., cov: 32)
• Consequence: TUBB3 NM_006086.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.804
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-89932386-G-A is Benign according to our data. Variant chr16-89932386-G-A is described in ClinVar as Benign. ClinVar VariationId is 670258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB3	NM_006086.4	c.58-185G>A		intron_variant	Intron 1 of 3	ENST00000315491.12	NP_006077.2
TUBB3	NM_001197181.2	c.-159-185G>A		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.58-185G>A		intron_variant	Intron 1 of 3	1	NM_006086.4	ENSP00000320295.7
ENSG00000198211	ENST00000556922.1	c.1099-185G>A		intron_variant	Intron 2 of 4	2		ENSP00000451560.1

Frequencies

GnomAD3 genomes AF: 0.329 AC: 50051 AN: 151934 Hom.: 8769 Cov.: 32

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.312

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.329 AC: 50097 AN: 152052 Hom.: 8784 Cov.: 32 AF XY: 0.341 AC XY: 25327 AN XY: 74310

African (AFR) AF: 0.302 AC: 12521 AN: 41490

American (AMR) AF: 0.420 AC: 6410 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 796 AN: 3468

East Asian (EAS) AF: 0.627 AC: 3238 AN: 5162

South Asian (SAS) AF: 0.449 AC: 2163 AN: 4816

European-Finnish (FIN) AF: 0.429 AC: 4540 AN: 10572

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19446 AN: 67964

Other (OTH) AF: 0.313 AC: 659 AN: 2106

Alfa AF: 0.303 Hom.: 17023

Bravo AF: 0.328

Asia WGS AF: 0.492 AC: 1715 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.1
DANN	Benign	0.78
PhyloP100		0.80
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2302898; hg19: chr16-89998794;