X-9688111-G-C

Variant names:

• chrX-9688111-G-C
• rs755145975
• NM_005647.4:c.452G>C

Variant summary

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

The NM_005647.4(TBL1X):​c.452G>C​(p.Arg151Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R151L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: TBL1X NM_005647.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.75
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hypothyroidism, congenital, nongoitrous, 8

  Inheritance: XL, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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	c.452G>C	p.Arg151Pro	missense_variant	Exon 7 of 18	ENST00000645353.2	NP_005638.1
TBL1X	NM_001139466.1	c.452G>C	p.Arg151Pro	missense_variant	Exon 7 of 18		NP_001132938.1
TBL1X	NM_001139467.1	c.299G>C	p.Arg100Pro	missense_variant	Exon 6 of 17		NP_001132939.1
TBL1X	NM_001139468.1	c.299G>C	p.Arg100Pro	missense_variant	Exon 7 of 18		NP_001132940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL1X	ENST00000645353.2	c.452G>C	p.Arg151Pro	missense_variant	Exon 7 of 18		NM_005647.4	ENSP00000496215.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T;.;T;T;T;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;.;.;.;.;.;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.7	.;M;.;M;M;M;M;.;.
PhyloP100		5.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.0	N;N;N;N;.;.;.;.;.
REVEL	Benign	0.20
Sift	Uncertain	0.022	D;D;D;D;.;.;.;.;.
Sift4G	Uncertain	0.030	D;D;D;D;.;.;.;.;.
Polyphen		0.88	.;P;.;P;P;P;P;.;.
Vest4		0.70
MutPred		0.42		.;Loss of MoRF binding (P = 0.0114);.;Loss of MoRF binding (P = 0.0114);Loss of MoRF binding (P = 0.0114);Loss of MoRF binding (P = 0.0114);Loss of MoRF binding (P = 0.0114);.;.;
MVP		0.70
MPC		1.3
ClinPred		0.95	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.91
Mutation Taster		=35/65	disease causing

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

Other links and lift over

dbSNP: rs755145975; hg19: chrX-9656151;