X-9653599-G-A

Variant names:

• chrX-9653599-G-A
• rs138597617
• NM_005647.4:c.13G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005647.4(TBL1X):​c.13G>A​(p.Ala5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000474 in 1,055,907 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A5P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000047 (0 hom. 1 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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04185173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBL1X	NM_005647.4	c.13G>A	p.Ala5Thr	missense_variant	Exon 4 of 18	ENST00000645353.2	NP_005638.1
TBL1X	NM_001139466.1	c.13G>A	p.Ala5Thr	missense_variant	Exon 4 of 18		NP_001132938.1
TBL1X	NM_001139467.1	c.-50-616G>A		intron_variant	Intron 3 of 16		NP_001132939.1
TBL1X	NM_001139468.1	c.-50-616G>A		intron_variant	Intron 4 of 17		NP_001132940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL1X	ENST00000645353.2	c.13G>A	p.Ala5Thr	missense_variant	Exon 4 of 18		NM_005647.4	ENSP00000496215.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000474 AC: 5 AN: 1055907 Hom.: 0 Cov.: 30 AF XY: 0.00000290 AC XY: 1 AN XY: 344987

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25010

American (AMR) AF: 0.00 AC: 0 AN: 28399

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18623

East Asian (EAS) AF: 0.0000367 AC: 1 AN: 27239

South Asian (SAS) AF: 0.00 AC: 0 AN: 49893

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4094

European-Non Finnish (NFE) AF: 0.00000488 AC: 4 AN: 820506

Other (OTH) AF: 0.00 AC: 0 AN: 44485

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000173), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 7

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 01, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports 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	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.053
DANN	Benign	0.74
DEOGEN2	Benign	0.20	T;T;T;T;T;T;T
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.49	T;T;.;.;.;.;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.042	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;N;N;N;N;.
PhyloP100		-3.6
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.0	N;N;N;.;.;.;N
REVEL	Benign	0.17
Sift	Benign	0.36	T;T;T;.;.;.;T
Sift4G	Benign	1.0	T;T;T;.;.;.;T
Polyphen		0.0	B;.;B;B;B;B;.
Vest4		0.046
MutPred		0.15		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.65
MPC		0.70
ClinPred		0.19	T
GERP RS		-2.6
Varity_R		0.036
gMVP		0.10
Mutation Taster		=98/2	polymorphism

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

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Other links and lift over

dbSNP: rs138597617; hg19: chrX-9621639;