rs115847686

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018943.3(TUBA8):c.250C>T(p.Arg84Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,614,136 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R84H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0053 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00055 ( 7 hom. )

Consequence

TUBA8
NM_018943.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.09

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

polymicrogyria with optic nerve hypoplasia
Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

TUBA8 links:

ENSG00000288683 (HGNC:):

ENSG00000288683 links:

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 (MetaRNN=0.010679781).

BP6

Variant 22-18124179-C-T is Benign according to our data. Variant chr22-18124179-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 160171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0053 (807/152260) while in subpopulation AFR AF = 0.0186 (771/41542). AF 95% confidence interval is 0.0175. There are 7 homozygotes in GnomAd4. There are 356 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA8	NM_018943.3 link	c.250C>T	p.Arg84Cys	missense_variant	Exon 3 of 5	ENST00000330423.8	NP_061816.1	Q9NY65-1
TUBA8	NM_001193414.2 link	c.52C>T	p.Arg18Cys	missense_variant	Exon 3 of 5		NP_001180343.1	Q9NY65-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TUBA8	ENST00000330423.8 link	c.250C>T	p.Arg84Cys	missense_variant	Exon 3 of 5	1	NM_018943.3	ENSP00000333326.3	Q9NY65-1
ENSG00000288683	ENST00000474897.6 link	n.*140C>T		non_coding_transcript_exon_variant	Exon 7 of 9	5		ENSP00000434235.2	E9PRC5
ENSG00000288683	ENST00000474897.6 link	n.*140C>T		3_prime_UTR_variant	Exon 7 of 9	5		ENSP00000434235.2	E9PRC5

Frequencies

GnomAD3 genomes

AF:

0.00528

AC:

804

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0185

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00137

AC:

345

AN:

251446

AF XY:

0.000986

show subpopulations

Gnomad AFR exome

AF:

0.0194

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000553

AC:

809

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

342

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0193

AC:

647

AN:

33478

American (AMR)

AF:

0.000872

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000342

AC:

AN:

1112010

Other (OTH)

AF:

0.00128

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00530

AC:

807

AN:

152260

Hom.:

Cov.:

AF XY:

0.00478

AC XY:

356

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0186

AC:

771

AN:

41542

American (AMR)

AF:

0.00157

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68004

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

126

168

210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00231

Hom.:

Bravo

AF:

0.00606

ESP6500AA

AF:

0.0188

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00166

AC:

202

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Sep 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 23, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 13, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

.;.;D;T

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

D;D;D;D

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Uncertain

-0.031

MutationAssessor

Pathogenic

2.9

.;.;M;.

PhyloP100

2.1

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-7.0

D;D;D;D

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

.;.;D;D

Sift4G

Uncertain

0.038

D;T;T;T

Polyphen

0.98, 0.10

.;.;D;B

Vest4

0.60, 0.62

MVP

0.87

MPC

0.83

ClinPred

0.099

GERP RS

4.1

Varity_R

0.66

gMVP

0.59

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over