3-177038112-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_024665.7(TBL1XR1):​c.1108G>A​(p.Asp370Asn) 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. D370Y) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

TBL1XR1
NM_024665.7 missense

Scores

10
7
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.83
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-177038112-C-A is described in Lovd as [Pathogenic].
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, 0.957
PP5
Variant 3-177038112-C-T is Pathogenic according to our data. Variant chr3-177038112-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TBL1XR1NM_024665.7 linkuse as main transcriptc.1108G>A p.Asp370Asn missense_variant 12/16 ENST00000457928.7 NP_078941.2 Q9BZK7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TBL1XR1ENST00000457928.7 linkuse as main transcriptc.1108G>A p.Asp370Asn missense_variant 12/161 NM_024665.7 ENSP00000413251.3 Q9BZK7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxOct 30, 2024Not 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: 35982159, 33057194, 36403551, 34490615, 29777588) -
Likely pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2022TBL1XR1: PM2, PM5, PP2, PP3, PS4:Supporting -
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 16, 2019- -
Pierpont syndrome Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingSchool of Pediatrics, Henan University of Chinese Medicine, Henan University Of Chinese Medicine-- -
Intellectual disability Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingDiagnostic Laboratory, Strasbourg University HospitalSep 10, 2020- -
Intellectual disability, autosomal dominant 41 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterFeb 23, 2023PS4_Moderate, PM2, PM5_Supporting, PM6_Strong, PP2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
T;T
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
.;D
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Uncertain
0.76
D
MutationAssessor
Pathogenic
3.6
H;H
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-4.7
D;D
REVEL
Pathogenic
0.83
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.019
D;D
Polyphen
0.96
D;D
Vest4
0.94
MutPred
0.85
Loss of ubiquitination at K374 (P = 0.1778);Loss of ubiquitination at K374 (P = 0.1778);
MVP
0.92
MPC
1.9
ClinPred
0.99
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.83
gMVP
0.91

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

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

Other links and lift over

dbSNP: rs1057517933; hg19: chr3-176755900; COSMIC: COSV70501537; COSMIC: COSV70501537; API