16-89932544-AC-ACC

Variant names:

• chr16-89932544-A-AC
• rs112388869
• NM_006086.4:c.58-20dupC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_006086.4(TUBB3):​c.58-20dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,596,432 control chromosomes in the GnomAD database, including 655 homozygotes. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.021 (49 hom., cov: 33)
  • Exomes 𝑓: 0.022 (606 hom.)
• Consequence: TUBB3 NM_006086.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.186
• Publications: 2 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 -10 ACMG points.

• BP6: Variant 16-89932544-A-AC is Benign according to our data. Variant chr16-89932544-A-AC is described in ClinVar as Benign. ClinVar VariationId is 1175481.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0793 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.58-20dupC		intron	N/A	NP_006077.2	Q13509-1
	TUBB3	NM_001197181.2		c.-159-20dupC		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.58-20dupC		intron	N/A	ENSP00000320295.7	Q13509-1
	ENSG00000198211	ENST00000556922.1	TSL:2	c.1099-20dupC		intron	N/A	ENSP00000451560.1	A0A0B4J269
	TUBB3	ENST00000557262.5	TSL:1	n.*41-20dupC		intron	N/A	ENSP00000451985.1	G3V4U2

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3134 AN: 150300 Hom.: 47 Cov.: 33

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.00991

Gnomad AMR AF: 0.0182

Gnomad ASJ AF: 0.0286

Gnomad EAS AF: 0.00255

Gnomad SAS AF: 0.0860

Gnomad FIN AF: 0.00842

Gnomad MID AF: 0.0160

Gnomad NFE AF: 0.0194

Gnomad OTH AF: 0.0233

GnomAD2 exomes AF: 0.0239 AC: 5966 AN: 249880 AF XY: 0.0269

Gnomad AFR exome AF: 0.0214

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.0285

Gnomad EAS exome AF: 0.00218

Gnomad FIN exome AF: 0.0101

Gnomad NFE exome AF: 0.0176

Gnomad OTH exome AF: 0.0239

GnomAD4 exome AF: 0.0217 AC: 31333 AN: 1446020 Hom.: 606 Cov.: 28 AF XY: 0.0234 AC XY: 16858 AN XY: 720354

African (AFR) AF: 0.0209 AC: 691 AN: 33138

American (AMR) AF: 0.0128 AC: 573 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 689 AN: 26044

East Asian (EAS) AF: 0.00134 AC: 53 AN: 39626

South Asian (SAS) AF: 0.0795 AC: 6837 AN: 85948

European-Finnish (FIN) AF: 0.0105 AC: 558 AN: 52978

Middle Eastern (MID) AF: 0.0360 AC: 207 AN: 5744

European-Non Finnish (NFE) AF: 0.0184 AC: 20220 AN: 1098014

Other (OTH) AF: 0.0252 AC: 1505 AN: 59830

GnomAD4 genome AF: 0.0209 AC: 3144 AN: 150412 Hom.: 49 Cov.: 33 AF XY: 0.0207 AC XY: 1521 AN XY: 73354

African (AFR) AF: 0.0217 AC: 892 AN: 41194

American (AMR) AF: 0.0184 AC: 275 AN: 14986

Ashkenazi Jewish (ASJ) AF: 0.0286 AC: 99 AN: 3458

East Asian (EAS) AF: 0.00255 AC: 13 AN: 5092

South Asian (SAS) AF: 0.0862 AC: 406 AN: 4712

European-Finnish (FIN) AF: 0.00842 AC: 86 AN: 10210

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0194 AC: 1307 AN: 67476

Other (OTH) AF: 0.0250 AC: 52 AN: 2084

Alfa AF: 0.0138 Hom.: 4

Asia WGS AF: 0.0480 AC: 167 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.19
La Branchor		0.82
BranchPoint Hunter		3.0
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: rs112388869; hg19: chr16-89998952; COSMIC: COSV59249020; COSMIC: COSV59249020;