NM_005647.4:c.1237-3C>G

Variant names:

• chrX-9709245-C-G
• rs199823517
• NM_005647.4:c.1237-3C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_005647.4(TBL1X):​c.1237-3C>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000155 in 1,096,894 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000015 (0 hom. 5 hem.)
• Consequence: TBL1X NM_005647.4 splice_region, intron
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.72
• Publications: 0 publications found

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]

TBL1X Gene-Disease associations (from GenCC):

• hypothyroidism, congenital, nongoitrous, 8

  Inheritance: XL, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBL1X	NM_005647.4	c.1237-3C>G		splice_region_variant, intron_variant	Intron 13 of 17	ENST00000645353.2	NP_005638.1
TBL1X	NM_001139466.1	c.1237-3C>G		splice_region_variant, intron_variant	Intron 13 of 17		NP_001132938.1
TBL1X	NM_001139467.1	c.1084-3C>G		splice_region_variant, intron_variant	Intron 12 of 16		NP_001132939.1
TBL1X	NM_001139468.1	c.1084-3C>G		splice_region_variant, intron_variant	Intron 13 of 17		NP_001132940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL1X	ENST00000645353.2	c.1237-3C>G		splice_region_variant, intron_variant	Intron 13 of 17		NM_005647.4	ENSP00000496215.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000155 AC: 17 AN: 1096894 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 5 AN XY: 362482

African (AFR) AF: 0.00 AC: 0 AN: 26376

American (AMR) AF: 0.00 AC: 0 AN: 35189

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19374

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.00 AC: 0 AN: 54038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40513

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3761

European-Non Finnish (NFE) AF: 0.0000202 AC: 17 AN: 841425

Other (OTH) AF: 0.00 AC: 0 AN: 46026

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Nov 03, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -

Jan 08, 2018

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing;provider interpretation

This 3 year old male has a history of autism spectrum disorder, developmental delays, macrocephaly (greater than 99th percentile), and a repaired ureteropelvic junction obstruction. He also carries a copy number gain involving a portion of GRIN2A, that is maternally inherited and categorized as a variant of uncertain significance. TBL1X is a gene of uncertain significance; no known human disorders have been clearly associated with this gene, although an association with autism spectrum disorders has been suggested (Chung et al., 2011). This variant is intronic and is predicted to damage the splice acceptor site in intron 12. This variant is maternally inherited. The patient's mother reports a history of anxiety and no other neurodevelopmental history. This variant is absent from gnomAD, however many other splice site variants are reported in the same region. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Benign	0.89
PhyloP100		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: -36
DS_AL_spliceai		0.41		Position offset: 3

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

Other links and lift over

dbSNP: rs199823517; hg19: chrX-9677285;