16-89932550-C-G

Position:

• chr16-89932550-C-G

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.58-21C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0048 in 1,608,064 control chromosomes in the GnomAD database, including 244 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (125 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (119 hom.)
• Consequence: TUBB3 NM_006086.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.01

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=-0.79).
• BP6: Variant 16-89932550-C-G is Benign according to our data. Variant chr16-89932550-C-G is described in ClinVar as [Benign]. Clinvar id is 1227568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89932550-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB3	NM_006086.4	c.58-21C>G		intron_variant		ENST00000315491.12	NP_006077.2
TUBB3	NM_001197181.2	c.-159-21C>G		intron_variant			NP_001184110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB3	ENST00000315491.12	c.58-21C>G		intron_variant		1	NM_006086.4	ENSP00000320295	P1

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3578 AN: 152216 Hom.: 125 Cov.: 33

Gnomad AFR AF: 0.0796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00692 AC: 1731 AN: 250308 Hom.: 56 AF XY: 0.00549 AC XY: 744 AN XY: 135588

Gnomad AFR exome AF: 0.0826

Gnomad AMR exome AF: 0.00307

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000363

Gnomad OTH exome AF: 0.00458

GnomAD4 exome AF: 0.00284 AC: 4129 AN: 1455730 Hom.: 119 Cov.: 30 AF XY: 0.00255 AC XY: 1847 AN XY: 724594

Gnomad4 AFR exome AF: 0.0816

Gnomad4 AMR exome AF: 0.00353

Gnomad4 ASJ exome AF: 0.0215

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.000320

Gnomad4 NFE exome AF: 0.000207

Gnomad4 OTH exome AF: 0.00663

GnomAD4 genome AF: 0.0235 AC: 3583 AN: 152334 Hom.: 125 Cov.: 33 AF XY: 0.0233 AC XY: 1732 AN XY: 74482

Gnomad4 AFR AF: 0.0795

Gnomad4 AMR AF: 0.00804

Gnomad4 ASJ AF: 0.0288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00332 Hom.: 2

Bravo AF: 0.0262

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.50
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs78656983; hg19: chr16-89998958;