22-18121480-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_018943.3(TUBA8):c.5G>A(p.Arg2Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,738 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

TUBA8
NM_018943.3 missense, splice_region

Scores

Splicing: ADA: 0.9641

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

TUBA8 (HGNC:12410): (tubulin alpha 8) This gene encodes a member of the alpha tubulin protein family. Alpha tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. Mutations in this gene are associated with polymicrogyria and optic nerve hypoplasia. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2010]

TUBA8 links:

ENSG00000288683 (HGNC:):

ENSG00000288683 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA8	NM_018943.3 link	c.5G>A	p.Arg2Gln	missense_variant, splice_region_variant	Exon 2 of 5	ENST00000330423.8	NP_061816.1	Q9NY65-1
TUBA8	NM_001193414.2 link	c.-194G>A		splice_region_variant	Exon 2 of 5		NP_001180343.1	Q9NY65-2
TUBA8	NM_001193414.2 link	c.-194G>A		5_prime_UTR_variant	Exon 2 of 5		NP_001180343.1	Q9NY65-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA8	ENST00000330423.8 link	c.5G>A	p.Arg2Gln	missense_variant, splice_region_variant	Exon 2 of 5	1	NM_018943.3	ENSP00000333326.3		Q9NY65-1
ENSG00000288683	ENST00000474897.6 link	n.816G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 9	5		ENSP00000434235.2		E9PRC5

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251336

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461578

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727092

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polymicrogyria with optic nerve hypoplasia

Uncertain:1

Apr 19, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:1

Jun 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2 of the TUBA8 protein (p.Arg2Gln). This variant is present in population databases (rs761087286, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with TUBA8-related conditions. ClinVar contains an entry for this variant (Variation ID: 1033914). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

T;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.62

D;D

MetaSVM

Uncertain

0.51

MutationAssessor

Pathogenic

3.7

H;.

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.0

N;N

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.032

D;D

Polyphen

0.028

B;D

Vest4

0.93

MutPred

0.67

.;Gain of disorder (P = 0.1255);

MVP

0.96

MPC

0.81

ClinPred

0.97

GERP RS

5.1

Varity_R

0.55

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Pathogenic

0.80

SpliceAI score (max)

0.96

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.96

Position offset: 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