X-9688032-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005647.4(TBL1X):c.373G>A(p.Asp125Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000332 in 1,205,346 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

TBL1X
NM_005647.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 8.82

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBL1X	NM_005647.4 link	c.373G>A	p.Asp125Asn	missense_variant	Exon 7 of 18	ENST00000645353.2	NP_005638.1	O60907-1A0A024RBV9
TBL1X	NM_001139466.1 link	c.373G>A	p.Asp125Asn	missense_variant	Exon 7 of 18		NP_001132938.1	O60907-1A0A024RBV9
TBL1X	NM_001139467.1 link	c.220G>A	p.Asp74Asn	missense_variant	Exon 6 of 17		NP_001132939.1	O60907-2
TBL1X	NM_001139468.1 link	c.220G>A	p.Asp74Asn	missense_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.373G>A	p.Asp125Asn	missense_variant	Exon 7 of 18		NM_005647.4	ENSP00000496215.1		O60907-1

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112050

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1093296

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

359642

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26314

American (AMR)

AF:

0.00

AC:

AN:

34843

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19029

East Asian (EAS)

AF:

0.00

AC:

AN:

30098

South Asian (SAS)

AF:

0.00

AC:

AN:

53273

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4114

European-Non Finnish (NFE)

AF:

0.00000357

AC:

AN:

839419

Other (OTH)

AF:

0.00

AC:

AN:

45878

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000892

AC:

AN:

112050

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34214

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30814

American (AMR)

AF:

0.00

AC:

AN:

10579

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2655

East Asian (EAS)

AF:

0.00

AC:

AN:

3560

South Asian (SAS)

AF:

0.00

AC:

AN:

2672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53182

Other (OTH)

AF:

0.00

AC:

AN:

1503

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Feb 08, 2023

Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

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

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.86

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

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.47

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

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.5

.;L;.;.;L;L;L;L;.;.

PhyloP100

8.8

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-2.0

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

REVEL

Benign

0.20

Sift

Benign

0.081

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

Sift4G

Benign

0.21

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

Polyphen

0.76

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

Vest4

0.81

MutPred

0.47

.;Loss of loop (P = 0.0374);.;.;Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);.;.;

MVP

0.81

MPC

1.0

ClinPred

0.90

GERP RS

4.9

Varity_R

0.47

gMVP

0.93

Mutation Taster

=44/56

disease causing

(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-9688032-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over