3-177026243-GAAAA-GAAAAAAAA

Variant names:

• chr3-177026243-G-GAAAA
• rs3046447
• NM_024665.7:c.1518+126_1518+129dupTTTT

Variant summary

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

The NM_024665.7(TBL1XR1):​c.1518+126_1518+129dupTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 468,370 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TBL1XR1 NM_024665.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.787
• 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: 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBL1XR1	NM_024665.7	c.1518+126_1518+129dupTTTT		intron_variant	Intron 15 of 15	ENST00000457928.7	NP_078941.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL1XR1	ENST00000457928.7	c.1518+129_1518+130insTTTT		intron_variant	Intron 15 of 15	1	NM_024665.7	ENSP00000413251.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000214 AC: 1 AN: 468370 Hom.: 0 AF XY: 0.00000403 AC XY: 1 AN XY: 248112

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 9984

American (AMR) AF: 0.00 AC: 0 AN: 11206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13918

East Asian (EAS) AF: 0.00 AC: 0 AN: 23372

South Asian (SAS) AF: 0.0000268 AC: 1 AN: 37308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2132

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 312078

Other (OTH) AF: 0.00 AC: 0 AN: 24182

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.79

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3046447; hg19: chr3-176744031;