rs77191445

Positions:

• chr16-89933586-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006086.4(TUBB3):​c.277+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00698 in 1,607,286 control chromosomes in the GnomAD database, including 653 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (354 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (299 hom.)
• Consequence: TUBB3 NM_006086.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001848
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.43

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-89933586-C-T is Benign according to our data. Variant chr16-89933586-C-T is described in ClinVar as [Benign]. Clinvar id is 137856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89933586-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB3	NM_006086.4	c.277+8C>T		splice_region_variant, intron_variant		ENST00000315491.12
TUBB3	NM_001197181.2	c.61+8C>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB3	ENST00000315491.12	c.277+8C>T		splice_region_variant, intron_variant		1	NM_006086.4	P1

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 5614 AN: 152098 Hom.: 351 Cov.: 33

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0272

GnomAD3 exomes AF: 0.00968 AC: 2433 AN: 251304 Hom.: 142 AF XY: 0.00718 AC XY: 975 AN XY: 135840

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.00711

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00384 AC: 5582 AN: 1455070 Hom.: 299 Cov.: 29 AF XY: 0.00331 AC XY: 2401 AN XY: 724344

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.00767

Gnomad4 ASJ exome AF: 0.000690

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.00962

GnomAD4 genome AF: 0.0370 AC: 5638 AN: 152216 Hom.: 354 Cov.: 33 AF XY: 0.0360 AC XY: 2678 AN XY: 74438

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.0140

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0156 Hom.: 62

Bravo AF: 0.0424

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.74
DANN	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0
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: rs77191445; hg19: chr16-89999994;