rs145621219

Positions:

chr22-18126726-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP4_StrongBP6_Very_StrongBS2

The NM_018943.3(TUBA8):c.748G>A(p.Val250Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,614,128 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0019 ( 24 hom. )

Consequence

TUBA8
NM_018943.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PrimateAI, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PROVEAN was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.01633808).

BP6

Variant 22-18126726-G-A is Benign according to our data. Variant chr22-18126726-G-A is described in ClinVar as [Benign]. Clinvar id is 137851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 24 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA8	NM_018943.3 linkuse as main transcript	c.748G>A	p.Val250Met	missense_variant	4/5	ENST00000330423.8
TUBA8	NM_001193414.2 linkuse as main transcript	c.550G>A	p.Val184Met	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA8	ENST00000330423.8 linkuse as main transcript	c.748G>A	p.Val250Met	missense_variant	4/5	1	NM_018943.3	P1	Q9NY65-1
	ENST00000623543.1 linkuse as main transcript	n.4429C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.00295

AC:

448

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0227

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00269

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00345

AC:

868

AN:

251486

Hom.:

AF XY:

0.00318

AC XY:

432

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0248

Gnomad NFE exome

AF:

0.00247

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00194

AC:

2838

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

1434

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00283

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0238

Gnomad4 NFE exome

AF:

0.00125

Gnomad4 OTH exome

AF:

0.00166

GnomAD4 genome

AF:

0.00294

AC:

448

AN:

152234

Hom.:

Cov.:

AF XY:

0.00382

AC XY:

284

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0227

Gnomad4 NFE

AF:

0.00269

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00241

Hom.:

Bravo

AF:

0.00109

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00314

AC:

381

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00158

EpiControl

AF:

0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 15, 2016

- -

TUBA8-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

.;T;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

MetaRNN

Benign

0.016

T;T;T

MetaSVM

Uncertain

0.64

MutationAssessor

Uncertain

2.3

.;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.2

N;N;N

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

.;D;D

Sift4G

Uncertain

0.026

D;D;D

Polyphen

0.99, 1.0

.;D;D

Vest4

0.86

MVP

0.99

MPC

0.88

ClinPred

0.066

GERP RS

5.7

Varity_R

0.48

gMVP

0.64

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