X-9653599-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_005647.4(TBL1X):c.13G>T(p.Ala5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,168,648 control chromosomes in the GnomAD database, including 8 homozygotes. There are 330 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A5P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0050 ( 4 hom., 161 hem., cov: 23)

Exomes 𝑓: 0.00062 ( 4 hom. 169 hem. )

Consequence

TBL1X
NM_005647.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -3.57

Variant links:

Genes affected

TBL1X (HGNC:11585): (transducin beta like 1 X-linked) The protein encoded by this gene has sequence similarity with members of the WD40 repeat-containing protein family. The WD40 group is a large family of proteins, which appear to have a regulatory function. It is believed that the WD40 repeats mediate protein-protein interactions and members of the family are involved in signal transduction, RNA processing, gene regulation, vesicular trafficking, cytoskeletal assembly and may play a role in the control of cytotypic differentiation. This encoded protein is found as a subunit in corepressor SMRT (silencing mediator for retinoid and thyroid receptors) complex along with histone deacetylase 3 protein. This gene is located adjacent to the ocular albinism gene and it is thought to be involved in the pathogenesis of the ocular albinism with late-onset sensorineural deafness phenotype. Four transcript variants encoding two different isoforms have been found for this gene. This gene is highly similar to the Y chromosome TBL1Y gene. [provided by RefSeq, Nov 2008]

TBL1X links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034570694).

BP6

Variant X-9653599-G-T is Benign according to our data. Variant chrX-9653599-G-T is described in ClinVar as [Benign]. Clinvar id is 720639.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.005 (564/112741) while in subpopulation AFR AF = 0.0169 (526/31089). AF 95% confidence interval is 0.0157. There are 4 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBL1X	NM_005647.4 link	c.13G>T	p.Ala5Ser	missense_variant	Exon 4 of 18	ENST00000645353.2	NP_005638.1	O60907-1A0A024RBV9
TBL1X	NM_001139466.1 link	c.13G>T	p.Ala5Ser	missense_variant	Exon 4 of 18		NP_001132938.1	O60907-1A0A024RBV9
TBL1X	NM_001139467.1 link	c.-50-616G>T		intron_variant	Intron 3 of 16		NP_001132939.1	O60907-2
TBL1X	NM_001139468.1 link	c.-50-616G>T		intron_variant	Intron 4 of 17		NP_001132940.1	O60907-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL1X	ENST00000645353.2 link	c.13G>T	p.Ala5Ser	missense_variant	Exon 4 of 18		NM_005647.4	ENSP00000496215.1		O60907-1

Frequencies

GnomAD3 genomes

AF:

0.00501

AC:

564

AN:

112687

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0170

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00224

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.0000750

Gnomad OTH

AF:

0.00593

GnomAD2 exomes

AF:

0.00145

AC:

170

AN:

116880

AF XY:

0.000985

show subpopulations

Gnomad AFR exome

AF:

0.0191

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000438

Gnomad OTH exome

AF:

0.000602

GnomAD4 exome

AF:

0.000620

AC:

655

AN:

1055907

Hom.:

Cov.:

AF XY:

0.000490

AC XY:

169

AN XY:

344987

show subpopulations

African (AFR)

AF:

0.0201

AC:

503

AN:

25010

American (AMR)

AF:

0.000916

AC:

AN:

28399

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18623

East Asian (EAS)

AF:

0.00

AC:

AN:

27239

South Asian (SAS)

AF:

0.00

AC:

AN:

49893

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37658

Middle Eastern (MID)

AF:

0.00293

AC:

AN:

4094

European-Non Finnish (NFE)

AF:

0.0000524

AC:

AN:

820506

Other (OTH)

AF:

0.00160

AC:

AN:

44485

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00500

AC:

564

AN:

112741

Hom.:

Cov.:

AF XY:

0.00461

AC XY:

161

AN XY:

34915

show subpopulations

African (AFR)

AF:

0.0169

AC:

526

AN:

31089

American (AMR)

AF:

0.00224

AC:

AN:

10720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3573

South Asian (SAS)

AF:

0.00

AC:

AN:

2752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6210

Middle Eastern (MID)

AF:

0.00457

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0000750

AC:

AN:

53305

Other (OTH)

AF:

0.00586

AC:

AN:

1536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000203

Hom.:

Bravo

AF:

0.00576

ESP6500AA

AF:

0.0171

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00135

AC:

136

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

TBL1X-related disorder

Benign:1

Jul 30, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

not provided

Benign:1

Nov 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.0020

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.20

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

FATHMM_MKL

Benign

0.0051

LIST_S2

Benign

0.50

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

MetaRNN

Benign

0.0035

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.;N;N;N;N;.

PhyloP100

-3.6

PrimateAI

Benign

0.25

PROVEAN

Benign

0.010

N;N;N;.;.;.;N

REVEL

Benign

0.13

Sift

Benign

0.071

T;T;T;.;.;.;D

Sift4G

Benign

0.15

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

Polyphen

0.0

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

Vest4

0.068

MVP

0.62

MPC

0.66

ClinPred

0.0071

GERP RS

-2.6

Varity_R

0.062

gMVP

0.063

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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X-9653599-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over