rs878854402

Positions:

• chr3-177033050-T-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000457928.7(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. Y446D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBL1XR1 ENST00000457928.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.67

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000457928.7
• 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-C is described in ClinVar as [Pathogenic]. Clinvar id is 559571.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TBL1XR1. . Gene score misZ 4.2042 (greater than the threshold 3.09). Trascript score misZ 5.2877 (greater than threshold 3.09). GenCC has associacion of gene with Pierpont syndrome, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 41.
• 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 id is 225874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-177033050-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBL1XR1	NM_024665.7	c.1337A>G	p.Tyr446Cys	missense_variant	14/16	ENST00000457928.7	NP_078941.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBL1XR1	ENST00000457928.7	c.1337A>G	p.Tyr446Cys	missense_variant	14/16	1	NM_024665.7	ENSP00000413251	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pierpont syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 29, 2023	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 225874). 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 variant is not present in population databases (gnomAD no frequency). 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). -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Oct 23, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 19, 2022	- -

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

Likely pathogenic, no assertion criteria provided

clinical testing

Wasik Lab, Fox Chase Cancer Center

Jul 25, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2024

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) -

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
MutationTaster	Benign	1.0	D;D
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

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

Publications

LitVar

Other links and lift over

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