rs77191445

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006086.4(TUBB3):​c.277+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00698 in 1,607,286 control chromosomes in the GnomAD database, including 653 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 354 hom., cov: 33)
Exomes 𝑓: 0.0038 ( 299 hom. )

Consequence

TUBB3
NM_006086.4 splice_region, intron

Scores

2
Splicing: ADA: 0.00001848
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.43

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.92).
BP6
Variant 16-89933586-C-T is Benign according to our data. Variant chr16-89933586-C-T is described in ClinVar as Benign. ClinVar VariationId is 137856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.126 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.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
TUBB3
NM_006086.4
MANE Select
c.277+8C>T
splice_region intron
N/ANP_006077.2Q13509-1
TUBB3
NM_001197181.2
c.61+8C>T
splice_region intron
N/ANP_001184110.1Q13509-2

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
TUBB3
ENST00000315491.12
TSL:1 MANE Select
c.277+8C>T
splice_region intron
N/AENSP00000320295.7Q13509-1
ENSG00000198211
ENST00000556922.1
TSL:2
c.1318+8C>T
splice_region intron
N/AENSP00000451560.1A0A0B4J269
TUBB3
ENST00000557262.5
TSL:1
n.*260+8C>T
splice_region intron
N/AENSP00000451985.1G3V4U2

Frequencies

GnomAD3 genomes
AF:
0.0369
AC:
5614
AN:
152098
Hom.:
351
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.128
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0140
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000827
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000412
Gnomad OTH
AF:
0.0272
GnomAD2 exomes
AF:
0.00968
AC:
2433
AN:
251304
AF XY:
0.00718
show subpopulations
Gnomad AFR exome
AF:
0.129
Gnomad AMR exome
AF:
0.00711
Gnomad ASJ exome
AF:
0.00129
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000361
Gnomad OTH exome
AF:
0.00473
GnomAD4 exome
AF:
0.00384
AC:
5582
AN:
1455070
Hom.:
299
Cov.:
29
AF XY:
0.00331
AC XY:
2401
AN XY:
724344
show subpopulations
African (AFR)
AF:
0.131
AC:
4368
AN:
33324
American (AMR)
AF:
0.00767
AC:
343
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.000690
AC:
18
AN:
26096
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39674
South Asian (SAS)
AF:
0.000302
AC:
26
AN:
86126
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53346
Middle Eastern (MID)
AF:
0.00781
AC:
45
AN:
5762
European-Non Finnish (NFE)
AF:
0.000184
AC:
203
AN:
1105860
Other (OTH)
AF:
0.00962
AC:
579
AN:
60164
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
331
661
992
1322
1653
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
130
260
390
520
650
<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
AF:
0.0370
AC:
5638
AN:
152216
Hom.:
354
Cov.:
33
AF XY:
0.0360
AC XY:
2678
AN XY:
74438
show subpopulations
African (AFR)
AF:
0.129
AC:
5333
AN:
41492
American (AMR)
AF:
0.0140
AC:
214
AN:
15294
Ashkenazi Jewish (ASJ)
AF:
0.000288
AC:
1
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.000621
AC:
3
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.000412
AC:
28
AN:
68012
Other (OTH)
AF:
0.0270
AC:
57
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
248
496
743
991
1239
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
56
112
168
224
280
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0156
Hom.:
62
Bravo
AF:
0.0424
Asia WGS
AF:
0.00751
AC:
26
AN:
3478
EpiCase
AF:
0.000491
EpiControl
AF:
0.000474

ClinVar

ClinVar submissions
Significance:Benign
Revision:criteria provided, multiple submitters, no conflicts
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
-
5
not specified (5)
-
-
2
not provided (2)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.92
CADD
Benign
0.74
DANN
Benign
0.43
PhyloP100
-1.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=100/0
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000018
dbscSNV1_RF
Benign
0.0
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

Other links and lift over

dbSNP: rs77191445; hg19: chr16-89999994; API
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.