X-9688157-T-TGCGGCC

Variant names:

• chrX-9688157-T-TGCGGCC
• rs1197487342
• NM_005647.4:c.499_504dupGCGGCC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP3 BS2

The NM_005647.4(TBL1X):​c.499_504dupGCGGCC​(p.Ala167_Ala168dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,083,556 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000021 (0 hom. 5 hem.)
• Consequence: TBL1X NM_005647.4 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04

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 -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005647.4
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBL1X	NM_005647.4	c.499_504dupGCGGCC	p.Ala167_Ala168dup	conservative_inframe_insertion	Exon 7 of 18	ENST00000645353.2	NP_005638.1
TBL1X	NM_001139466.1	c.499_504dupGCGGCC	p.Ala167_Ala168dup	conservative_inframe_insertion	Exon 7 of 18		NP_001132938.1
TBL1X	NM_001139467.1	c.346_351dupGCGGCC	p.Ala116_Ala117dup	conservative_inframe_insertion	Exon 6 of 17		NP_001132939.1
TBL1X	NM_001139468.1	c.346_351dupGCGGCC	p.Ala116_Ala117dup	conservative_inframe_insertion	Exon 7 of 18		NP_001132940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL1X	ENST00000645353.2	c.499_504dupGCGGCC	p.Ala167_Ala168dup	conservative_inframe_insertion	Exon 7 of 18		NM_005647.4	ENSP00000496215.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.0000212 AC: 23 AN: 1083556 Hom.: 0 Cov.: 32 AF XY: 0.0000142 AC XY: 5 AN XY: 353298

Gnomad4 AFR exome AF: 0.00

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: 0.0000275

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

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 21, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame insertion of 2 amino acids in a repetitive region with no known function; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1197487342; hg19: chrX-9656197;