X-9653626-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005647.4(TBL1X):c.40C>T(p.Arg14Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000264 in 1,172,156 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.000018 ( 0 hom. 8 hem. )

Consequence

TBL1X
NM_005647.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.125

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.062436163).

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBL1X	NM_005647.4 link	c.40C>T	p.Arg14Cys	missense_variant	Exon 4 of 18	ENST00000645353.2	NP_005638.1	O60907-1A0A024RBV9
TBL1X	NM_001139466.1 link	c.40C>T	p.Arg14Cys	missense_variant	Exon 4 of 18		NP_001132938.1	O60907-1A0A024RBV9
TBL1X	NM_001139467.1 link	c.-50-589C>T		intron_variant	Intron 3 of 16		NP_001132939.1	O60907-2
TBL1X	NM_001139468.1 link	c.-50-589C>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.40C>T	p.Arg14Cys	missense_variant	Exon 4 of 18		NM_005647.4	ENSP00000496215.1		O60907-1

Frequencies

GnomAD3 genomes

AF:

0.000107

AC:

AN:

112676

Hom.:

Cov.:

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:

0.000483

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000169

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000574

AC:

AN:

121887

AF XY:

0.0000735

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000253

Gnomad NFE exome

AF:

0.0000621

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1059480

Hom.:

Cov.:

AF XY:

0.0000231

AC XY:

AN XY:

346118

show subpopulations

African (AFR)

AF:

0.0000398

AC:

AN:

25141

American (AMR)

AF:

0.00

AC:

AN:

29126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18689

East Asian (EAS)

AF:

0.00

AC:

AN:

27409

South Asian (SAS)

AF:

0.0000400

AC:

AN:

50046

European-Finnish (FIN)

AF:

0.000211

AC:

AN:

37999

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4101

European-Non Finnish (NFE)

AF:

0.00000730

AC:

AN:

822362

Other (OTH)

AF:

0.0000448

AC:

AN:

44607

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000107

AC:

AN:

112676

Hom.:

Cov.:

AF XY:

0.0000574

AC XY:

AN XY:

34816

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31026

American (AMR)

AF:

0.00

AC:

AN:

10678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3581

South Asian (SAS)

AF:

0.00

AC:

AN:

2743

European-Finnish (FIN)

AF:

0.000483

AC:

AN:

6210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.000169

AC:

AN:

53339

Other (OTH)

AF:

0.00

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000282

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 22, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.40C>T (p.R14C) alteration is located in exon 4 (coding exon 1) of the TBL1X gene. This alteration results from a C to T substitution at nucleotide position 40, causing the arginine (R) at amino acid position 14 to be replaced by a cysteine (C). 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

0.16

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

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

FATHMM_MKL

Benign

0.0084

LIST_S2

Benign

0.72

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

M_CAP

Benign

0.013

MetaRNN

Benign

0.062

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

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

PhyloP100

-0.13

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.11

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

REVEL

Benign

0.11

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.48

P;.;P;P;P;P;.

Vest4

0.17

MVP

0.35

MPC

1.7

ClinPred

0.13

GERP RS

-0.61

Varity_R

0.11

gMVP

0.41

Mutation Taster

=100/0

polymorphism

(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-9653626-C-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