X-9653599-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005647.4(TBL1X):c.13G>T(p.Ala5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,168,648 control chromosomes in the GnomAD database, including 8 homozygotes. There are 330 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A5T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., 161 hem., cov: 23)
  • Exomes 𝑓: 0.00062 (4 hom. 169 hem.)
• Consequence: TBL1X NM_005647.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034570694).
• BP6: Variant X-9653599-G-T is Benign according to our data. Variant chrX-9653599-G-T is described in ClinVar as [Benign]. Clinvar id is 720639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.005 (564/112741) while in subpopulation AFR AF= 0.0169 (526/31089). AF 95% confidence interval is 0.0157. There are 4 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBL1X	NM_005647.4	c.13G>T	p.Ala5Ser	missense_variant	4/18	ENST00000645353.2
TBL1X	NM_001139466.1	c.13G>T	p.Ala5Ser	missense_variant	4/18
TBL1X	NM_001139467.1	c.-50-616G>T		intron_variant
TBL1X	NM_001139468.1	c.-50-616G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBL1X	ENST00000645353.2	c.13G>T	p.Ala5Ser	missense_variant	4/18		NM_005647.4

Frequencies

GnomAD3 genomes AF: 0.00501 AC: 564 AN: 112687 Hom.: 4 Cov.: 23 AF XY: 0.00462 AC XY: 161 AN XY: 34851

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00224

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.0000750

Gnomad OTH AF: 0.00593

GnomAD3 exomes AF: 0.00145 AC: 170 AN: 116880 Hom.: 2 AF XY: 0.000985 AC XY: 39 AN XY: 39612

Gnomad AFR exome AF: 0.0191

Gnomad AMR exome AF: 0.00116

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: 0.0000438

Gnomad OTH exome AF: 0.000602

GnomAD4 exome AF: 0.000620 AC: 655 AN: 1055907 Hom.: 4 Cov.: 30 AF XY: 0.000490 AC XY: 169 AN XY: 344987

Gnomad4 AFR exome AF: 0.0201

Gnomad4 AMR exome AF: 0.000916

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: 0.0000524

Gnomad4 OTH exome AF: 0.00160

GnomAD4 genome AF: 0.00500 AC: 564 AN: 112741 Hom.: 4 Cov.: 23 AF XY: 0.00461 AC XY: 161 AN XY: 34915

Gnomad4 AFR AF: 0.0169

Gnomad4 AMR AF: 0.00224

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000750

Gnomad4 OTH AF: 0.00586

Alfa AF: 0.000203 Hom.: 7

Bravo AF: 0.00576

ESP6500AA AF: 0.0171 AC: 65

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00135 AC: 136

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TBL1X-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.0020
Dann	Benign	0.77
DEOGEN2	Benign	0.20	T;T;T;T;T;T;T
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.50	T;T;.;.;.;.;T
MetaRNN	Benign	0.0035	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	0.25	T
PROVEAN	Benign	0.010	N;N;N;.;.;.;N
REVEL	Benign	0.13
Sift	Benign	0.071	T;T;T;.;.;.;D
Sift4G	Benign	0.15	T;T;T;.;.;.;T
Polyphen		0.0	B;.;B;B;B;B;.
Vest4		0.068
MVP		0.62
MPC		0.66
ClinPred		0.0071	T
GERP RS		-2.6
Varity_R		0.062
gMVP		0.063

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: rs138597617; hg19: chrX-9621639;