rs1553810255

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5

The ENST00000457928.7(TBL1XR1):​c.974G>A​(p.Cys325Tyr) 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TBL1XR1
ENST00000457928.7 missense

Scores

14
4
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 7.87
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-AS1 (HGNC:41243): (TBL1XR1 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a hotspot region, there are 5 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;
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, 0.928
PP5
Variant 3-177038386-C-T is Pathogenic according to our data. Variant chr3-177038386-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 545441.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TBL1XR1NM_024665.7 linkuse as main transcriptc.974G>A p.Cys325Tyr missense_variant 11/16 ENST00000457928.7 NP_078941.2
TBL1XR1-AS1NR_174966.1 linkuse as main transcriptn.365C>T non_coding_transcript_exon_variant 2/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TBL1XR1ENST00000457928.7 linkuse as main transcriptc.974G>A p.Cys325Tyr missense_variant 11/161 NM_024665.7 ENSP00000413251 P1
TBL1XR1-AS1ENST00000617758.1 linkuse as main transcriptn.365C>T non_coding_transcript_exon_variant 2/45

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1427338
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
706500
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 41 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMay 05, 2020This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneDec 08, 2016- -
Pierpont syndrome Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 13, 2019- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 01, 2023Not 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: 37683765, 31298310, 30365874, 36691917, 36843287, 33527360, 32449767, 32034290) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.60
D;D
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
.;D
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.93
D;D
MetaSVM
Uncertain
0.69
D
MutationAssessor
Pathogenic
3.0
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-9.4
D;D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.87
MutPred
0.77
Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);
MVP
0.95
MPC
3.0
ClinPred
1.0
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.97
gMVP
0.96

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553810255; hg19: chr3-176756174; COSMIC: COSV70501007; COSMIC: COSV70501007; API