3-177038129-A-C

Variant names:

• chr3-177038129-A-C
• NM_024665.7:c.1091T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_024665.7(TBL1XR1):​c.1091T>G​(p.Leu364Trp) 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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.23

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)

ACMG classification

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, 0.903
• PP5: Variant 3-177038129-A-C is Pathogenic according to our data. Variant chr3-177038129-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3383964.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	c.1091T>G	p.Leu364Trp	missense_variant	Exon 12 of 16	ENST00000457928.7	NP_078941.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL1XR1	ENST00000457928.7	c.1091T>G	p.Leu364Trp	missense_variant	Exon 12 of 16	1	NM_024665.7	ENSP00000413251.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

TBL1XR1-related neurodevelopmental disorder Pathogenic:1

Dec 06, 2024

Molecular Genetics Laboratory, Motol Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was detected in a male with developmental delay, delayed speech and language development, dyslalia, abnormal behavior, facial dysmorphism. The variant was confirmed to be of a de novo origin. Rare missense variants affecting the TBL1XR1 gene are documented as a molecular cause of autosomal dominant "intellectual developmental disorder-41" (MRD41, OMIM:616944) and Pierpont syndrome (PRPTS, OMIM:602342) (PMID:38378692;33527360;32524419;30365874). To conclude, the variant is classified as likely pathogenic (ACMG PS2, PM2, PM1, PP2, PP3). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	32
DANN	Benign	0.96
DEOGEN2	Uncertain	0.51	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.60		Gain of catalytic residue at L364 (P = 0.2952);Gain of catalytic residue at L364 (P = 0.2952);
MVP		0.93
MPC		2.9
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
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.

Other links and lift over

hg19: chr3-176755917;