X-9688096-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005647.4(TBL1X):c.437G>T(p.Arg146Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R146W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: TBL1X NM_005647.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBL1X	NM_005647.4	c.437G>T	p.Arg146Leu	missense_variant	7/18	ENST00000645353.2
TBL1X	NM_001139466.1	c.437G>T	p.Arg146Leu	missense_variant	7/18
TBL1X	NM_001139467.1	c.284G>T	p.Arg95Leu	missense_variant	6/17
TBL1X	NM_001139468.1	c.284G>T	p.Arg95Leu	missense_variant	7/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBL1X	ENST00000645353.2	c.437G>T	p.Arg146Leu	missense_variant	7/18		NM_005647.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2024

The c.437G>T (p.R146L) alteration is located in exon 7 (coding exon 4) of the TBL1X gene. This alteration results from a G to T substitution at nucleotide position 437, causing the arginine (R) at amino acid position 146 to be replaced by a leucine (L). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	27
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;.;.;.;.;.;D;D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.0	D;D;D;D;.;.;.;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.086	T;D;T;D;.;.;.;.;.
Sift4G	Uncertain	0.059	T;D;T;D;.;.;.;.;.
Polyphen		0.94	.;P;.;P;P;P;P;.;.
Vest4		0.80
MutPred		0.47		.;Loss of solvent accessibility (P = 0.0299);.;Loss of solvent accessibility (P = 0.0299);Loss of solvent accessibility (P = 0.0299);Loss of solvent accessibility (P = 0.0299);Loss of solvent accessibility (P = 0.0299);.;.;
MVP		0.78
MPC		1.7
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-9656136;