Genetic Variant TBL1XR1:c.1518+129dupT (chr3-177026243-G-GA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_024665.7(TBL1XR1):c.1518+129dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 587,356 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 22)

Exomes 𝑓: 0.031 ( 0 hom. )

Consequence

TBL1XR1
NM_024665.7 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.787

Publications

0 publications found

Variant links:

Genes affected

TBL1XR1 (HGNC:29529): (TBL1X/Y related 1) This gene is a member of the WD40 repeat-containing gene family and shares sequence similarity with transducin (beta)-like 1X-linked (TBL1X). The protein encoded by this gene is thought to be a component of both nuclear receptor corepressor (N-CoR) and histone deacetylase 3 (HDAC 3) complexes, and is required for transcriptional activation by a variety of transcription factors. Mutations in these gene have been associated with some autism spectrum disorders, and one finding suggests that haploinsufficiency of this gene may be a cause of intellectual disability with dysmorphism. Mutations in this gene as well as recurrent translocations involving this gene have also been observed in some tumors. [provided by RefSeq, Mar 2016]

TBL1XR1 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
intellectual disability, autosomal dominant 41
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Pierpont syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

TBL1XR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBL1XR1	NM_024665.7 link	c.1518+129dupT		intron_variant	Intron 15 of 15	ENST00000457928.7	NP_078941.2	Q9BZK7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL1XR1	ENST00000457928.7 link	c.1518+129_1518+130insT		intron_variant	Intron 15 of 15	1	NM_024665.7	ENSP00000413251.3		Q9BZK7

Frequencies

GnomAD3 genomes

AF:

0.000436

AC:

AN:

146808

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000124

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00129

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000786

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000322

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000498

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0314

AC:

13841

AN:

440456

Hom.:

AF XY:

0.0322

AC XY:

7508

AN XY:

232888

show subpopulations

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

African (AFR)

AF:

0.0240

AC:

229

AN:

9526

American (AMR)

AF:

0.0347

AC:

368

AN:

10598

Ashkenazi Jewish (ASJ)

AF:

0.0312

AC:

405

AN:

12988

East Asian (EAS)

AF:

0.0157

AC:

354

AN:

22510

South Asian (SAS)

AF:

0.0457

AC:

1558

AN:

34090

European-Finnish (FIN)

AF:

0.0223

AC:

722

AN:

32410

Middle Eastern (MID)

AF:

0.0379

AC:

AN:

2006

European-Non Finnish (NFE)

AF:

0.0321

AC:

9425

AN:

293716

Other (OTH)

AF:

0.0311

AC:

704

AN:

22612

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.256

Heterozygous variant carriers

1799

3598

5398

7197

8996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000436

AC:

AN:

146900

Hom.:

Cov.:

AF XY:

0.000420

AC XY:

AN XY:

71416

show subpopulations

African (AFR)

AF:

0.000124

AC:

AN:

40324

American (AMR)

AF:

0.00128

AC:

AN:

14794

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3394

East Asian (EAS)

AF:

0.000788

AC:

AN:

5078

South Asian (SAS)

AF:

0.00

AC:

AN:

4624

European-Finnish (FIN)

AF:

0.000322

AC:

AN:

9306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000499

AC:

AN:

66192

Other (OTH)

AF:

0.00

AC:

AN:

2016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000310

Hom.:

152

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.79

Mutation Taster

=100/0

polymorphism

(source)

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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3-177026243-GAAAA-GAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over