Genetic Variant TBL1X:p.Ala166Ala (chrX-9688157-T-G) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_005647.4(TBL1X):c.498T>G(p.Ala166Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000785 in 1,195,525 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 265 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., 14 hem., cov: 24)

Exomes 𝑓: 0.00081 ( 0 hom. 251 hem. )

Consequence

TBL1X
NM_005647.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -4.11

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant X-9688157-T-G is Benign according to our data. Variant chrX-9688157-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2659951.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-9688157-T-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-4.11 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBL1X	NM_005647.4 link	c.498T>G	p.Ala166Ala	synonymous_variant	Exon 7 of 18	ENST00000645353.2	NP_005638.1	O60907-1A0A024RBV9
TBL1X	NM_001139466.1 link	c.498T>G	p.Ala166Ala	synonymous_variant	Exon 7 of 18		NP_001132938.1	O60907-1A0A024RBV9
TBL1X	NM_001139467.1 link	c.345T>G	p.Ala115Ala	synonymous_variant	Exon 6 of 17		NP_001132939.1	O60907-2
TBL1X	NM_001139468.1 link	c.345T>G	p.Ala115Ala	synonymous_variant	Exon 7 of 18		NP_001132940.1	O60907-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL1X	ENST00000645353.2 link	c.498T>G	p.Ala166Ala	synonymous_variant	Exon 7 of 18		NM_005647.4	ENSP00000496215.1		O60907-1

Frequencies

GnomAD3 genomes

AF:

0.000562

AC:

AN:

112022

Hom.:

Cov.:

AF XY:

0.000409

AC XY:

AN XY:

34224

show subpopulations

Gnomad AFR

AF:

0.0000650

Gnomad AMI

AF:

0.00291

Gnomad AMR

AF:

0.0000943

Gnomad ASJ

AF:

0.000376

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000435

AC:

AN:

149516

Hom.:

AF XY:

0.000549

AC XY:

AN XY:

47328

show subpopulations

Gnomad AFR exome

AF:

0.000204

Gnomad AMR exome

AF:

0.000122

Gnomad ASJ exome

AF:

0.000145

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000121

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000894

Gnomad OTH exome

AF:

0.000258

GnomAD4 exome

AF:

0.000808

AC:

876

AN:

1083503

Hom.:

Cov.:

AF XY:

0.000711

AC XY:

251

AN XY:

353245

show subpopulations

Gnomad4 AFR exome

AF:

0.000193

Gnomad4 AMR exome

AF:

0.0000899

Gnomad4 ASJ exome

AF:

0.000209

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000571

Gnomad4 FIN exome

AF:

0.0000777

Gnomad4 NFE exome

AF:

0.000995

Gnomad4 OTH exome

AF:

0.000594

GnomAD4 genome

AF:

0.000562

AC:

AN:

112022

Hom.:

Cov.:

AF XY:

0.000409

AC XY:

AN XY:

34224

show subpopulations

Gnomad4 AFR

AF:

0.0000650

Gnomad4 AMR

AF:

0.0000943

Gnomad4 ASJ

AF:

0.000376

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00107

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000327

Hom.:

Bravo

AF:

0.000499

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TBL1X: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.10

DANN

Benign

0.29

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