rs786205859

Positions:

• chr3-177051722-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Moderate

The NM_024665.7(TBL1XR1):​c.209G>A​(p.Gly70Asp) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G70C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TBL1XR1 NM_024665.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.53

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 10 ACMG points.

• PM1: In a domain F-box-like (size 45) in uniprot entity TBL1R_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chr3-177051723-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2628582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, TBL1XR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812
• PP5: Variant 3-177051722-C-T is Pathogenic according to our data. Variant chr3-177051722-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191371.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBL1XR1	NM_024665.7	c.209G>A	p.Gly70Asp	missense_variant	5/16	ENST00000457928.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBL1XR1	ENST00000457928.7	c.209G>A	p.Gly70Asp	missense_variant	5/16	1	NM_024665.7	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 28, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35165208, 33708771, 25102098, 26069883, 26740553, 28588275, 30365874, 26769062, 32034290, 28687524, 26482601, 32449767, 31394400, 33527360, 35611576, 33490948) -

Intellectual disability, autosomal dominant 41 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;D;.;T;T;T;T;T;T;.;.;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.2	M;M;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.2	D;D;D;D;.;.;D;.;.;D;D;D;.
REVEL	Pathogenic	0.78
Sift	Benign	0.13	T;T;D;D;.;.;D;.;.;T;T;T;.
Sift4G	Benign	0.14	T;T;.;.;.;.;D;.;.;.;.;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.93
MutPred		0.35		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.72
MPC		2.5
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs786205859; hg19: chr3-176769510;