chr3-177050010-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5

The NM_024665.7(TBL1XR1):​c.689C>T​(p.Ser230Phe) 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)

Consequence

TBL1XR1
NM_024665.7 missense

Scores

13
4
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 10.0
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 Likely_pathogenic. Variant got 6 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). The gene has 50 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. GenCC has associacion of the gene with Pierpont syndrome, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 41.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.897
PP5
Variant 3-177050010-G-A is Pathogenic according to our data. Variant chr3-177050010-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521029.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TBL1XR1NM_024665.7 linkc.689C>T p.Ser230Phe missense_variant 7/16 ENST00000457928.7 NP_078941.2 Q9BZK7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TBL1XR1ENST00000457928.7 linkc.689C>T p.Ser230Phe missense_variant 7/161 NM_024665.7 ENSP00000413251.3 Q9BZK7

Frequencies

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

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 12, 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: 32371413) -
Pierpont syndrome;C4310784:Intellectual disability, autosomal dominant 41 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInstitute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's HospitalJan 15, 2018[ACMG/AMP: PS2, PM2, PP2, PP3] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is absent from or rarely observed in large-scale population databases [PM2], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3]. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 20, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
T;T
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
.;D
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.90
D;D
MetaSVM
Uncertain
0.074
D
MutationAssessor
Pathogenic
3.2
M;M
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-4.5
D;D
REVEL
Pathogenic
0.69
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.013
D;D
Polyphen
1.0
D;D
Vest4
0.91
MutPred
0.64
Loss of disorder (P = 0.0116);Loss of disorder (P = 0.0116);
MVP
0.95
MPC
2.4
ClinPred
0.99
D
GERP RS
5.2
Varity_R
0.90
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: rs1553815393; hg19: chr3-176767798; API