chrX-9684186-G-A

Position:

chrX-9684186-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005647.4(TBL1X):c.355G>A(p.Glu119Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000909 in 1,210,083 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000091 ( 0 hom. 3 hem. )

Consequence

TBL1X
NM_005647.4 missense, splice_region

Scores

Splicing: ADA: 0.4810

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.31

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 Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TBL1X	NM_005647.4 linkuse as main transcript	c.355G>A	p.Glu119Lys	missense_variant, splice_region_variant	6/18	ENST00000645353.2
TBL1X	NM_001139466.1 linkuse as main transcript	c.355G>A	p.Glu119Lys	missense_variant, splice_region_variant	6/18
TBL1X	NM_001139467.1 linkuse as main transcript	c.202G>A	p.Glu68Lys	missense_variant, splice_region_variant	5/17
TBL1X	NM_001139468.1 linkuse as main transcript	c.202G>A	p.Glu68Lys	missense_variant, splice_region_variant	6/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBL1X	ENST00000645353.2 linkuse as main transcript	c.355G>A	p.Glu119Lys	missense_variant, splice_region_variant	6/18		NM_005647.4		O60907-1

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

111987

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34157

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000911

AC:

AN:

1098096

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

363450

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000831

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.00000893

AC:

AN:

111987

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34157

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

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

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D;.;D;.;.;.;.;D;D

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.69

D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.3

.;M;.;.;M;M;M;M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.5

N;N;N;D;N;.;.;.;.;.

REVEL

Uncertain

0.38

Sift

Uncertain

0.024

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

Sift4G

Benign

0.071

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

Polyphen

0.20

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

Vest4

0.73

MutPred

0.49

.;Gain of ubiquitination at E119 (P = 0.0077);.;.;Gain of ubiquitination at E119 (P = 0.0077);Gain of ubiquitination at E119 (P = 0.0077);Gain of ubiquitination at E119 (P = 0.0077);Gain of ubiquitination at E119 (P = 0.0077);.;.;

MVP

0.90

MPC

0.89

ClinPred

0.97

GERP RS

4.6

Varity_R

0.68

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.48

dbscSNV1_RF

Benign

0.64

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