rs878854401

Positions:

• chr3-177047518-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_024665.7(TBL1XR1):​c.734A>G​(p.Tyr245Cys) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBL1XR1 NM_024665.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.99

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-AS1 (HGNC:41243): (TBL1XR1 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.763
• PP5: Variant 3-177047518-T-C is Pathogenic according to our data. Variant chr3-177047518-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-177047518-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.734A>G	p.Tyr245Cys	missense_variant	8/16	ENST00000457928.7	NP_078941.2
TBL1XR1-AS1	NR_174966.1	n.518-116T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBL1XR1	ENST00000457928.7	c.734A>G	p.Tyr245Cys	missense_variant	8/16	1	NM_024665.7	ENSP00000413251	P1
TBL1XR1-AS1	ENST00000617758.1	n.530-116T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pierpont syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2022	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 245 of the TBL1XR1 protein (p.Tyr245Cys). This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 225873). This missense change has been observed in individual(s) with clinical features of TBL1XR1-related conditions (PMID: 27133561; Invitae). In at least one individual the variant was observed to be de novo. -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 19, 2023

Not observed 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: 34758253, 27535533, 27133561) -

Intellectual disability, autosomal dominant 41 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.7	D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.066	T;T
Polyphen		0.23	B;B
Vest4		0.87
MutPred		0.34		Gain of glycosylation at S244 (P = 0.2706);Gain of glycosylation at S244 (P = 0.2706);
MVP		0.78
MPC		1.9
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.96

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: rs878854401; hg19: chr3-176765306;