rs755371824

Variant names:

• chr3-177033096-G-A
• rs755371824
• NM_024665.7:c.1291C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-177033096-G-A
• chr3-177033096-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024665.7(TBL1XR1):​c.1291C>T​(p.Arg431*) variant causes a stop gained change involving the alteration of a non-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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBL1XR1 NM_024665.7 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.12
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 41

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Pierpont syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-177033096-G-A is Pathogenic according to our data. Variant chr3-177033096-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 981384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024665.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBL1XR1	NM_024665.7	MANE Select	c.1291C>T	p.Arg431*	stop_gained	Exon 14 of 16	NP_078941.2
	TBL1XR1	NM_001321193.3		c.1291C>T	p.Arg431*	stop_gained	Exon 14 of 16	NP_001308122.1
	TBL1XR1	NM_001321194.3		c.1291C>T	p.Arg431*	stop_gained	Exon 15 of 17	NP_001308123.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBL1XR1	ENST00000457928.7	TSL:1 MANE Select	c.1291C>T	p.Arg431*	stop_gained	Exon 14 of 16	ENSP00000413251.3
	TBL1XR1	ENST00000430069.5	TSL:1	c.1291C>T	p.Arg431*	stop_gained	Exon 14 of 16	ENSP00000405574.1
	TBL1XR1	ENST00000352800.10	TSL:5	c.1291C>T	p.Arg431*	stop_gained	Exon 13 of 15	ENSP00000263964.11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability (1)
1	-	-	not provided (1)
1	-	-	Pierpont syndrome;C4310784:Intellectual disability, autosomal dominant 41 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.88	D
PhyloP100		2.1
Vest4		0.86
GERP RS		-0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=5/195	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs755371824; hg19: chr3-176750884; COSMIC: COSV101467823; COSMIC: COSV101467823;