chr3-177053847-C-T

Position:

• chr3-177053847-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_024665.7(TBL1XR1):​c.130G>A​(p.Val44Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TBL1XR1 NM_024665.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.91

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 Uncertain_significance. Variant got 4 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
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38728446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBL1XR1	NM_024665.7	c.130G>A	p.Val44Ile	missense_variant	4/16	ENST00000457928.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBL1XR1	ENST00000457928.7	c.130G>A	p.Val44Ile	missense_variant	4/16	1	NM_024665.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461416 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2017

- -

Pierpont syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 23, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 521844). This variant has not been reported in the literature in individuals affected with TBL1XR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 44 of the TBL1XR1 protein (p.Val44Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;.;T;T;T;T;T;T;.;.;T;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	.;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L;L;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.65	N;N;N;N;.;.;N;.;.;N;N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.17	T;T;T;T;.;.;T;.;.;T;T;T;T;T
Sift4G	Benign	0.11	T;T;.;.;.;.;T;.;.;.;.;.;.;.
Polyphen		0.99	D;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.47
MutPred		0.32		Gain of catalytic residue at P46 (P = 0.0625);Gain of catalytic residue at P46 (P = 0.0625);Gain of catalytic residue at P46 (P = 0.0625);Gain of catalytic residue at P46 (P = 0.0625);Gain of catalytic residue at P46 (P = 0.0625);.;Gain of catalytic residue at P46 (P = 0.0625);Gain of catalytic residue at P46 (P = 0.0625);Gain of catalytic residue at P46 (P = 0.0625);Gain of catalytic residue at P46 (P = 0.0625);Gain of catalytic residue at P46 (P = 0.0625);Gain of catalytic residue at P46 (P = 0.0625);Gain of catalytic residue at P46 (P = 0.0625);Gain of catalytic residue at P46 (P = 0.0625);
MVP		0.50
MPC		2.0
ClinPred		0.88	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.84

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: rs1553817638; hg19: chr3-176771635;