X-9688164-A-C

Position:

• chrX-9688164-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005647.4(TBL1X):​c.505A>C​(p.Thr169Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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: -0.256

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0780884).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBL1X	NM_005647.4	c.505A>C	p.Thr169Pro	missense_variant	7/18	ENST00000645353.2	NP_005638.1
TBL1X	NM_001139466.1	c.505A>C	p.Thr169Pro	missense_variant	7/18		NP_001132938.1
TBL1X	NM_001139467.1	c.352A>C	p.Thr118Pro	missense_variant	6/17		NP_001132939.1
TBL1X	NM_001139468.1	c.352A>C	p.Thr118Pro	missense_variant	7/18		NP_001132940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBL1X	ENST00000645353.2	c.505A>C	p.Thr169Pro	missense_variant	7/18		NM_005647.4	ENSP00000496215

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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 08, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter 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	Benign	0.068
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.99
DANN	Benign	0.37
DEOGEN2	Benign	0.22	.;T;.;T;T;T;T;.
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.16	T;T;.;.;.;.;.;T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.078	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;.;N;N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.48	N;N;N;N;.;.;.;.
REVEL	Benign	0.055
Sift	Benign	0.21	T;T;T;T;.;.;.;.
Sift4G	Benign	0.26	T;T;T;T;.;.;.;.
Polyphen		0.037	.;B;.;B;B;B;B;.
Vest4		0.14
MutPred		0.26		.;Loss of phosphorylation at T169 (P = 0.0344);.;Loss of phosphorylation at T169 (P = 0.0344);Loss of phosphorylation at T169 (P = 0.0344);Loss of phosphorylation at T169 (P = 0.0344);Loss of phosphorylation at T169 (P = 0.0344);.;
MVP		0.24
MPC		1.0
ClinPred		0.091	T
GERP RS		0.24
Varity_R		0.099
gMVP		0.61

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-9656204;