X-9653599-G-C

Position:

chrX-9653599-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005647.4(TBL1X):c.13G>C(p.Ala5Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,168,593 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000028 ( 0 hom. 2 hem. )

Consequence

TBL1X
NM_005647.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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 made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0658142).

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBL1X	NM_005647.4 link	c.13G>C	p.Ala5Pro	missense_variant	4/18	ENST00000645353.2	NP_005638.1	O60907-1A0A024RBV9
TBL1X	NM_001139466.1 link	c.13G>C	p.Ala5Pro	missense_variant	4/18		NP_001132938.1	O60907-1A0A024RBV9
TBL1X	NM_001139467.1 link	c.-50-616G>C		intron_variant			NP_001132939.1	O60907-2
TBL1X	NM_001139468.1 link	c.-50-616G>C		intron_variant			NP_001132940.1	O60907-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBL1X	ENST00000645353.2 link	c.13G>C	p.Ala5Pro	missense_variant	4/18		NM_005647.4	ENSP00000496215.1		O60907-1

Frequencies

GnomAD3 genomes

AF:

0.00000887

AC:

AN:

112687

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34851

show subpopulations

Gnomad AFR

AF:

0.0000322

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000284

AC:

AN:

1055906

Hom.:

Cov.:

AF XY:

0.00000580

AC XY:

AN XY:

344986

show subpopulations

Gnomad4 AFR exome

AF:

0.0000800

Gnomad4 AMR exome

AF:

0.0000352

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000887

AC:

AN:

112687

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34851

show subpopulations

Gnomad4 AFR

AF:

0.0000322

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2024

The c.13G>C (p.A5P) alteration is located in exon 4 (coding exon 1) of the TBL1X gene. This alteration results from a G to C substitution at nucleotide position 13, causing the alanine (A) at amino acid position 5 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.066

DANN

Benign

0.91

DEOGEN2

Benign

0.19

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

FATHMM_MKL

Benign

0.0023

LIST_S2

Benign

0.51

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

M_CAP

Benign

0.0086

MetaRNN

Benign

0.066

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

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

PrimateAI

Benign

0.26

PROVEAN

Benign

0.35

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

REVEL

Benign

0.18

Sift

Uncertain

0.026

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

Sift4G

Uncertain

0.046

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

Polyphen

0.063

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

Vest4

0.15

MutPred

0.16

Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);

MVP

0.78

MPC

0.93

ClinPred

0.093

GERP RS

-2.6

Varity_R

0.081

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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