X-9653626-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005647.4(TBL1X):c.40C>T(p.Arg14Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000264 in 1,172,156 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 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 0.00011 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.000018 (0 hom. 8 hem.)
• Consequence: TBL1X NM_005647.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.125

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.062436163).
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBL1X	NM_005647.4	c.40C>T	p.Arg14Cys	missense_variant	4/18	ENST00000645353.2
TBL1X	NM_001139466.1	c.40C>T	p.Arg14Cys	missense_variant	4/18
TBL1X	NM_001139467.1	c.-50-589C>T		intron_variant
TBL1X	NM_001139468.1	c.-50-589C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBL1X	ENST00000645353.2	c.40C>T	p.Arg14Cys	missense_variant	4/18		NM_005647.4

Frequencies

GnomAD3 genomes AF: 0.000107 AC: 12 AN: 112676 Hom.: 0 Cov.: 24 AF XY: 0.0000574 AC XY: 2 AN XY: 34816

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: 0.000483

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000169

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000574 AC: 7 AN: 121887 Hom.: 0 AF XY: 0.0000735 AC XY: 3 AN XY: 40825

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000696

Gnomad FIN exome AF: 0.000253

Gnomad NFE exome AF: 0.0000621

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000179 AC: 19 AN: 1059480 Hom.: 0 Cov.: 30 AF XY: 0.0000231 AC XY: 8 AN XY: 346118

Gnomad4 AFR exome AF: 0.0000398

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000400

Gnomad4 FIN exome AF: 0.000211

Gnomad4 NFE exome AF: 0.00000730

Gnomad4 OTH exome AF: 0.0000448

GnomAD4 genome AF: 0.000107 AC: 12 AN: 112676 Hom.: 0 Cov.: 24 AF XY: 0.0000574 AC XY: 2 AN XY: 34816

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000483

Gnomad4 NFE AF: 0.000169

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000282 AC: 3

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

Dec 22, 2023

The c.40C>T (p.R14C) alteration is located in exon 4 (coding exon 1) of the TBL1X gene. This alteration results from a C to T substitution at nucleotide position 40, causing the arginine (R) at amino acid position 14 to be replaced by a cysteine (C). 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	0.16
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	12
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T;T;T;T;T;T
FATHMM_MKL	Benign	0.0084	N
LIST_S2	Benign	0.72	T;T;.;.;.;.;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.062	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;N;N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.11	N;D;N;.;.;.;N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D;D;D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;.;.;.;D
Polyphen		0.48	P;.;P;P;P;P;.
Vest4		0.17
MVP		0.35
MPC		1.7
ClinPred		0.13	T
GERP RS		-0.61
Varity_R		0.11
gMVP		0.41

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: rs779687124; hg19: chrX-9621666;