rs878854402

Variant names:

• chr3-177033050-T-C
• rs878854402
• NM_024665.7:c.1337A>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_024665.7(TBL1XR1):​c.1337A>G​(p.Tyr446Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y446N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBL1XR1 NM_024665.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.67
• Publications: 39 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_024665.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-177033051-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1176162.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the TBL1XR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 50 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 4.2042 (above the threshold of 3.09). Trascript score misZ: 5.2877 (above the threshold of 3.09). GenCC associations: The gene is linked to complex neurodevelopmental disorder, intellectual disability, autosomal dominant 41, Pierpont syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892
• PP5: Variant 3-177033050-T-C is Pathogenic according to our data. Variant chr3-177033050-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 225874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBL1XR1	NM_024665.7	c.1337A>G	p.Tyr446Cys	missense_variant	Exon 14 of 16	ENST00000457928.7	NP_078941.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL1XR1	ENST00000457928.7	c.1337A>G	p.Tyr446Cys	missense_variant	Exon 14 of 16	1	NM_024665.7	ENSP00000413251.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pierpont syndrome Pathogenic:3

Oct 23, 2018

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with Pierpont syndrome (PMID: 26769062). In at least one individual the variant was observed to be de novo. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 446 of the TBL1XR1 protein (p.Tyr446Cys). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 225874). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TBL1XR1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Jul 19, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Malignant lymphoma, large B-cell, diffuse Pathogenic:1

Jul 25, 2023

Wasik Lab, Fox Chase Cancer Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant was observed in a patient with DLBCL that presented in leukemic form, best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. TBL1XR1 K398* and Y446C were detected in the tumor at presentation and after recurrence, with the K398* allele frequency doubling from 30% to 60%. These TBL1XR1 alterations result in the loss of interaction of the SMRT/NCOR1 complex with the germinal center transcriptional repressor BCL-6. Instead, BCL-6 binding to the transcription factor BACH2 complex is induced. This binding realignment blocks germinal-center B cells from developing into plasma cells by repressing PRDM1, a transcriptional repressor. Additionally, at relapse, this tumor had arm-level loss of 6q which contains PRDM1 (Figure 2). Inactivation of PRDM1 is critical to pathogenesis of ABC-DLBCL (Pasqualucci et al. 2006; Calado et al. 2010; Mandelbaum et al. 2010). Collectively, TBL1XR1 mutations and loss of PRDM1 prevent B-cell differentiation towards plasma cells and drive them toward the memory B-cell program (Venturutti and Melnick 2020; Venturutti et al. 2020), most likely contributing to malignant cell transformation. -

not provided Pathogenic:1

Jun 13, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31487502, 28771251, 28562391, 28687524, 35165208, 35032046, 33936649, 26769062) -

TBL1XR1-related disorder Pathogenic:1

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PS3, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.2	L;L
PhyloP100		7.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.6	D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		0.94	P;P
Vest4		0.89
MutPred		0.52		Loss of phosphorylation at Y446 (P = 0.0358);Loss of phosphorylation at Y446 (P = 0.0358);
MVP		0.85
MPC		2.5
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.76
gMVP		0.72
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs878854402; hg19: chr3-176750838; COSMIC: COSV70500760; COSMIC: COSV70500760;