16-89932240-T-G

Variant names:

• chr16-89932240-T-G
• rs58336812
• NM_006086.4:c.58-331T>G

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.58-331T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0578 in 415,250 control chromosomes in the GnomAD database, including 2,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (2137 hom., cov: 33)
  • Exomes 𝑓: 0.034 (675 hom.)
• Consequence: TUBB3 NM_006086.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.267
• Publications: 1 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=-0.83).
• BP6: Variant 16-89932240-T-G is Benign according to our data. Variant chr16-89932240-T-G is described in ClinVar as Benign. ClinVar VariationId is 1277879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.308 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.58-331T>G		intron	N/A	NP_006077.2	Q13509-1
	TUBB3	NM_001197181.2		c.-159-331T>G		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.58-331T>G		intron	N/A	ENSP00000320295.7	Q13509-1
	ENSG00000198211	ENST00000556922.1	TSL:2	c.1099-331T>G		intron	N/A	ENSP00000451560.1	A0A0B4J269
	TUBB3	ENST00000557262.5	TSL:1	n.*40+301T>G		intron	N/A	ENSP00000451985.1	G3V4U2

Frequencies

GnomAD3 genomes AF: 0.0984 AC: 14975 AN: 152132 Hom.: 2121 Cov.: 33

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0404

Gnomad ASJ AF: 0.0230

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.00885

Gnomad OTH AF: 0.0718

GnomAD4 exome AF: 0.0342 AC: 8993 AN: 263000 Hom.: 675 AF XY: 0.0393 AC XY: 5506 AN XY: 140002

African (AFR) AF: 0.318 AC: 2439 AN: 7662

American (AMR) AF: 0.0265 AC: 329 AN: 12418

Ashkenazi Jewish (ASJ) AF: 0.0195 AC: 147 AN: 7534

East Asian (EAS) AF: 0.00596 AC: 85 AN: 14264

South Asian (SAS) AF: 0.101 AC: 4127 AN: 40848

European-Finnish (FIN) AF: 0.00416 AC: 52 AN: 12488

Middle Eastern (MID) AF: 0.0605 AC: 63 AN: 1042

European-Non Finnish (NFE) AF: 0.00822 AC: 1253 AN: 152412

Other (OTH) AF: 0.0347 AC: 498 AN: 14332

GnomAD4 genome AF: 0.0987 AC: 15025 AN: 152250 Hom.: 2137 Cov.: 33 AF XY: 0.0967 AC XY: 7199 AN XY: 74466

African (AFR) AF: 0.312 AC: 12959 AN: 41506

American (AMR) AF: 0.0403 AC: 617 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0230 AC: 80 AN: 3472

East Asian (EAS) AF: 0.00463 AC: 24 AN: 5188

South Asian (SAS) AF: 0.112 AC: 539 AN: 4828

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10622

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.00885 AC: 602 AN: 68014

Other (OTH) AF: 0.0720 AC: 152 AN: 2112

Alfa AF: 0.0274 Hom.: 67

Bravo AF: 0.108

Asia WGS AF: 0.0740 AC: 256 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	10
DANN	Benign	0.75
PhyloP100		0.27
Mutation Taster		=300/0	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: rs58336812; hg19: chr16-89998648;