22-18126936-C-T

Position:

chr22-18126936-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BP4

The NM_018943.3(TUBA8):c.958C>T(p.Arg320Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000526 in 1,612,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 0 hom. )

Consequence

TUBA8
NM_018943.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 4.87

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.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.4061558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBA8	NM_018943.3 linkuse as main transcript	c.958C>T	p.Arg320Trp	missense_variant	4/5	ENST00000330423.8	NP_061816.1	Q9NY65-1
TUBA8	NM_001193414.2 linkuse as main transcript	c.760C>T	p.Arg254Trp	missense_variant	4/5		NP_001180343.1	Q9NY65-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TUBA8	ENST00000330423.8 linkuse as main transcript	c.958C>T	p.Arg320Trp	missense_variant	4/5	1	NM_018943.3	ENSP00000333326.3	Q9NY65-1
ENSG00000288683	ENST00000474897.6 linkuse as main transcript	n.*848C>T		non_coding_transcript_exon_variant	8/9	5		ENSP00000434235.2	E9PRC5
ENSG00000288683	ENST00000474897.6 linkuse as main transcript	n.*848C>T		3_prime_UTR_variant	8/9	5		ENSP00000434235.2	E9PRC5

Frequencies

GnomAD3 genomes

AF:

0.000349

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000625

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000516

AC:

129

AN:

250082

Hom.:

AF XY:

0.000496

AC XY:

AN XY:

135166

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00312

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000626

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000557

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000544

AC:

795

AN:

1460522

Hom.:

Cov.:

AF XY:

0.000553

AC XY:

402

AN XY:

726514

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00300

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000558

Gnomad4 FIN exome

AF:

0.0000937

Gnomad4 NFE exome

AF:

0.000533

Gnomad4 OTH exome

AF:

0.000812

GnomAD4 genome

AF:

0.000348

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000625

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000702

Hom.:

Bravo

AF:

0.000438

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000511

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.00131

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 16, 2023	PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34704371, 34853893, 34662886) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

Polymicrogyria with optic nerve hypoplasia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 26, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 02, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

.;D;D

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

4.9

.;H;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-6.3

D;D;D

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.96

MVP

1.0

MPC

0.91

ClinPred

0.58

GERP RS

3.5

Varity_R

0.90

gMVP

0.90

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