Variant 18-12308317-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_032525.3(TUBB6):c.25G>T(p.Ala9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000338 in 1,482,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A9A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

TUBB6
NM_032525.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.40

Variant links:

Genes affected

TUBB6 (HGNC:20776): (tubulin beta 6 class V) Predicted to enable GTP binding activity. Predicted to be a structural constituent of cytoskeleton. Predicted to be involved in microtubule cytoskeleton organization and mitotic cell cycle. Located in microtubule. [provided by Alliance of Genome Resources, Apr 2022]

TUBB6 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40769765).

BS2

High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB6	NM_032525.3 linkuse as main transcript	c.25G>T	p.Ala9Ser	missense_variant	1/4	ENST00000317702.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB6	ENST00000317702.10 linkuse as main transcript	c.25G>T	p.Ala9Ser	missense_variant	1/4	1	NM_032525.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000185

AC:

AN:

151164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000340

Gnomad OTH

AF:

0.000482

GnomAD3 exomes

AF:

0.000175

AC:

AN:

171280

Hom.:

AF XY:

0.000166

AC XY:

AN XY:

96212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000124

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000355

AC:

473

AN:

1331172

Hom.:

Cov.:

AF XY:

0.000340

AC XY:

225

AN XY:

661710

show subpopulations

Gnomad4 AFR exome

AF:

0.0000738

Gnomad4 AMR exome

AF:

0.0000903

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000222

Gnomad4 NFE exome

AF:

0.000429

Gnomad4 OTH exome

AF:

0.000358

GnomAD4 genome

AF:

0.000185

AC:

AN:

151164

Hom.:

Cov.:

AF XY:

0.000163

AC XY:

AN XY:

73796

show subpopulations

Gnomad4 AFR

AF:

0.0000726

Gnomad4 AMR

AF:

0.0000659

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000340

Gnomad4 OTH

AF:

0.000482

Alfa

AF:

0.000258

Hom.:

Bravo

AF:

0.000208

ExAC

AF:

0.000117

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2022

The c.25G>T (p.A9S) alteration is located in exon 1 (coding exon 1) of the TUBB6 gene. This alteration results from a G to T substitution at nucleotide position 25, causing the alanine (A) at amino acid position 9 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.23

Cadd

Benign

Dann

Benign

0.95

DEOGEN2

Benign

0.026

T;T;T;T;T;T;.;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.93

D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Benign

0.41

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.13

MutationTaster

Benign

0.90

D;D;D;D;D;D

PrimateAI

Pathogenic

0.84

Sift4G

Benign

0.097

T;T;T;T;T;T;D;D

Polyphen

0.20

.;B;.;.;.;.;.;.

Vest4

0.26, 0.25, 0.24, 0.26, 0.27

MVP

0.68

MPC

2.0

ClinPred

0.34

GERP RS

0.22

Varity_R

0.28

gMVP

0.44

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over