Variant 3-177038114-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_ModeratePP5_Moderate

The NM_024665.7(TBL1XR1):c.1106A>G(p.Asp369Gly) 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

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.94

Variant links:

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 links:

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

TBL1XR1-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 Pierpont syndrome, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 41.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.898

PP5

Variant 3-177038114-T-C is Pathogenic according to our data. Variant chr3-177038114-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2627906.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBL1XR1	NM_024665.7 link	c.1106A>G	p.Asp369Gly	missense_variant	Exon 12 of 16	ENST00000457928.7	NP_078941.2	Q9BZK7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL1XR1	ENST00000457928.7 link	c.1106A>G	p.Asp369Gly	missense_variant	Exon 12 of 16	1	NM_024665.7	ENSP00000413251.3		Q9BZK7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

TBL1XR1-related neurodevelopmental disorder

Pathogenic:1

Aug 04, 2023

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TBL1XR1 c.1106A>G (p.Asp369Gly) missense variant has not, to our knowledge, been reported in the peer-reviewed literature. However, another variant at the same amino acid position, c.1107C>A (p.Asp369Gly), classified as a variant of uncertain significance, has been reported in a heterozygous de novo state in an individual with a developmental disorder (PMID:31785789). The c.1106A>G variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The c.1106A>G variant is located in a known mutational hotspot (PMID: 32524419) with multiple lines of computational evidence suggesting the variant may impact the gene or gene product. This variant was identified in a de novo state. Based on the available evidence, the c.1106A>G (p.Asp369Gly) variant is classified as likely pathogenic for TBL1XR1-related neurodevelopmental disorder. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Benign

0.049

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Benign

-0.43

MutationAssessor

Benign

0.68

N;N

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-6.6

D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.023

D;D

Sift4G

Uncertain

0.046

D;D

Polyphen

0.99

D;D

Vest4

0.87

MutPred

0.59

Loss of stability (P = 0.0294);Loss of stability (P = 0.0294);

MVP

0.91

MPC

2.6

ClinPred

0.99

GERP RS

5.5

Varity_R

0.89

gMVP

0.85

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over