Genetic Variant NM_006086.4:c.58-20delC (chr16-89932544-AC-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_006086.4(TUBB3):c.58-20delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000332 in 1,446,144 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

TUBB3
NM_006086.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.186

Publications

2 publications found

Variant links:

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

TUBB3 links:

ENSG00000198211 (HGNC:):

ENSG00000198211 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000332 (48/1446144) while in subpopulation NFE AF = 0.0000419 (46/1098106). AF 95% confidence interval is 0.0000321. There are 0 homozygotes in GnomAdExome4. There are 23 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 48 AD gene.

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.58-20delC		intron	N/A	NP_006077.2	Q13509-1
	TUBB3	NM_001197181.2		c.-159-20delC		intron	N/A	NP_001184110.1	Q13509-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TUBB3	ENST00000315491.12	TSL:1 MANE Select	c.58-20delC	intron	N/A	ENSP00000320295.7	Q13509-1
ENSG00000198211	ENST00000556922.1	TSL:2	c.1099-20delC	intron	N/A	ENSP00000451560.1	A0A0B4J269
TUBB3	ENST00000557262.5	TSL:1	n.*41-20delC	intron	N/A	ENSP00000451985.1	G3V4U2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000800

AC:

AN:

249880

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000332

AC:

AN:

1446144

Hom.:

Cov.:

AF XY:

0.0000319

AC XY:

AN XY:

720406

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33140

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26048

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.00

AC:

AN:

85952

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52988

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000419

AC:

AN:

1098106

Other (OTH)

AF:

0.0000334

AC:

AN:

59842

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.19

La Branchor

0.82

BranchPoint Hunter

3.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over