X-9688147-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005647.4(TBL1X):c.488C>T(p.Ala163Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000918 in 1,198,766 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000083 (0 hom. 6 hem.)
• Consequence: TBL1X NM_005647.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.57

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22732607).
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBL1X	NM_005647.4	c.488C>T	p.Ala163Val	missense_variant	7/18	ENST00000645353.2
TBL1X	NM_001139466.1	c.488C>T	p.Ala163Val	missense_variant	7/18
TBL1X	NM_001139467.1	c.335C>T	p.Ala112Val	missense_variant	6/17
TBL1X	NM_001139468.1	c.335C>T	p.Ala112Val	missense_variant	7/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBL1X	ENST00000645353.2	c.488C>T	p.Ala163Val	missense_variant	7/18		NM_005647.4

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112208 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34368

Gnomad AFR AF: 0.0000324

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

GnomAD3 exomes AF: 0.0000193 AC: 3 AN: 155224 Hom.: 0 AF XY: 0.0000395 AC XY: 2 AN XY: 50684

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000152

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000828 AC: 9 AN: 1086558 Hom.: 0 Cov.: 32 AF XY: 0.0000169 AC XY: 6 AN XY: 354970

Gnomad4 AFR exome AF: 0.0000767

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000717

Gnomad4 OTH exome AF: 0.0000219

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112208 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34368

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

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

Apr 07, 2022

The c.488C>T (p.A163V) alteration is located in exon 7 (coding exon 4) of the TBL1X gene. This alteration results from a C to T substitution at nucleotide position 488, causing the alanine (A) at amino acid position 163 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	18
Dann	Uncertain	0.98
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D;D;.;.;.;.;.;T;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.1	N;N;N;N;.;.;.;.;.
REVEL	Benign	0.10
Sift	Benign	0.28	T;T;T;T;.;.;.;.;.
Sift4G	Benign	0.24	T;T;T;T;.;.;.;.;.
Polyphen		0.015	.;B;.;B;B;B;B;.;.
Vest4		0.27
MutPred		0.38		.;Gain of catalytic residue at A163 (P = 0.0904);.;Gain of catalytic residue at A163 (P = 0.0904);Gain of catalytic residue at A163 (P = 0.0904);Gain of catalytic residue at A163 (P = 0.0904);Gain of catalytic residue at A163 (P = 0.0904);.;.;
MVP		0.72
MPC		0.72
ClinPred		0.095	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.084
gMVP		0.35

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

LitVar

Other links and lift over

dbSNP: rs1236755685; hg19: chrX-9656187;