16-89932549-C-T

Variant names:

• chr16-89932549-C-T
• rs2302897
• NM_006086.4:c.58-22C>T

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.58-22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0882 in 1,607,320 control chromosomes in the GnomAD database, including 13,351 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (5057 hom., cov: 33)
  • Exomes 𝑓: 0.078 (8294 hom.)
• Consequence: TUBB3 NM_006086.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.623
• Publications: 5 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):

• TUBB3-related tubulinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• complex cortical dysplasia with other brain malformations 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Illumina, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement

  Inheritance: AD Classification: STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=-0.81).
• BP6: Variant 16-89932549-C-T is Benign according to our data. Variant chr16-89932549-C-T is described in ClinVar as Benign. ClinVar VariationId is 160192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006086.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB3	NM_006086.4	MANE Select	c.58-22C>T		intron	N/A	NP_006077.2	Q13509-1
	TUBB3	NM_001197181.2		c.-159-22C>T		intron	N/A	NP_001184110.1	Q13509-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB3	ENST00000315491.12	TSL:1 MANE Select	c.58-22C>T		intron	N/A	ENSP00000320295.7	Q13509-1
	ENSG00000198211	ENST00000556922.1	TSL:2	c.1099-22C>T		intron	N/A	ENSP00000451560.1	A0A0B4J269
	TUBB3	ENST00000557262.5	TSL:1	n.*41-22C>T		intron	N/A	ENSP00000451985.1	G3V4U2

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27880 AN: 152128 Hom.: 5038 Cov.: 33

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0962

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.0289

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.0701

Gnomad OTH AF: 0.172

GnomAD2 exomes AF: 0.0979 AC: 24491 AN: 250192 AF XY: 0.0942

Gnomad AFR exome AF: 0.477

Gnomad AMR exome AF: 0.0691

Gnomad ASJ exome AF: 0.0984

Gnomad EAS exome AF: 0.00125

Gnomad FIN exome AF: 0.0288

Gnomad NFE exome AF: 0.0741

Gnomad OTH exome AF: 0.0981

GnomAD4 exome AF: 0.0782 AC: 113777 AN: 1455076 Hom.: 8294 Cov.: 30 AF XY: 0.0791 AC XY: 57266 AN XY: 724326

African (AFR) AF: 0.487 AC: 16244 AN: 33330

American (AMR) AF: 0.0763 AC: 3412 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0983 AC: 2563 AN: 26082

East Asian (EAS) AF: 0.00804 AC: 319 AN: 39666

South Asian (SAS) AF: 0.125 AC: 10728 AN: 86112

European-Finnish (FIN) AF: 0.0321 AC: 1705 AN: 53110

Middle Eastern (MID) AF: 0.235 AC: 1356 AN: 5758

European-Non Finnish (NFE) AF: 0.0644 AC: 71280 AN: 1106204

Other (OTH) AF: 0.103 AC: 6170 AN: 60110

GnomAD4 genome AF: 0.183 AC: 27930 AN: 152244 Hom.: 5057 Cov.: 33 AF XY: 0.177 AC XY: 13215 AN XY: 74452

African (AFR) AF: 0.471 AC: 19560 AN: 41492

American (AMR) AF: 0.118 AC: 1811 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0962 AC: 334 AN: 3472

East Asian (EAS) AF: 0.00520 AC: 27 AN: 5188

South Asian (SAS) AF: 0.129 AC: 624 AN: 4830

European-Finnish (FIN) AF: 0.0289 AC: 307 AN: 10622

Middle Eastern (MID) AF: 0.298 AC: 87 AN: 292

European-Non Finnish (NFE) AF: 0.0701 AC: 4769 AN: 68020

Other (OTH) AF: 0.171 AC: 361 AN: 2114

Alfa AF: 0.0844 Hom.: 837

Bravo AF: 0.201

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.84
DANN	Benign	0.95
PhyloP100		-0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2302897; hg19: chr16-89998957;