chr3-177026370-T-C

Variant names:

• chr3-177026370-T-C
• NM_024665.7:c.1518+3A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024665.7(TBL1XR1):​c.1518+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBL1XR1 NM_024665.7 splice_region, intron
• Scores: Splicing: ADA: 0.5316
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Pierpont syndrome

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBL1XR1	NM_024665.7	MANE Select	c.1518+3A>G		splice_region intron	N/A	NP_078941.2
	TBL1XR1	NM_001321193.3		c.1518+3A>G		splice_region intron	N/A	NP_001308122.1	Q9BZK7
	TBL1XR1	NM_001321194.3		c.1518+3A>G		splice_region intron	N/A	NP_001308123.1	Q9BZK7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBL1XR1	ENST00000457928.7	TSL:1 MANE Select	c.1518+3A>G		splice_region intron	N/A	ENSP00000413251.3	Q9BZK7
	TBL1XR1	ENST00000430069.5	TSL:1	c.1518+3A>G		splice_region intron	N/A	ENSP00000405574.1	Q9BZK7
	TBL1XR1	ENST00000474363.1	TSL:1	n.1458+3A>G		splice_region intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Pierpont syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Benign	0.95
PhyloP100		1.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.53
dbscSNV1_RF	Benign	0.46
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

hg19: chr3-176744158;