3-177074378-G-A

Variant names:

• chr3-177074378-G-A
• rs1681655
• NM_024665.7:c.-45-9356C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024665.7(TBL1XR1):​c.-45-9356C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.932 in 152,306 control chromosomes in the GnomAD database, including 66,325 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.93 (66325 hom., cov: 32)
• Consequence: TBL1XR1 NM_024665.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.336
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

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.-45-9356C>T		intron	N/A	NP_078941.2
	TBL1XR1	NM_001321193.3		c.-45-9356C>T		intron	N/A	NP_001308122.1
	TBL1XR1	NM_001321194.3		c.-46+5449C>T		intron	N/A	NP_001308123.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBL1XR1	ENST00000457928.7	TSL:1 MANE Select	c.-45-9356C>T		intron	N/A	ENSP00000413251.3
	TBL1XR1	ENST00000430069.5	TSL:1	c.-45-9356C>T		intron	N/A	ENSP00000405574.1
	TBL1XR1	ENST00000352800.10	TSL:5	c.-45-9356C>T		intron	N/A	ENSP00000263964.11

Frequencies

GnomAD3 genomes AF: 0.932 AC: 141889 AN: 152188 Hom.: 66264 Cov.: 32

Gnomad AFR AF: 0.976

Gnomad AMI AF: 0.922

Gnomad AMR AF: 0.924

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.904

Gnomad SAS AF: 0.959

Gnomad FIN AF: 0.946

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.914

Gnomad OTH AF: 0.890

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.932 AC: 142008 AN: 152306 Hom.: 66325 Cov.: 32 AF XY: 0.933 AC XY: 69495 AN XY: 74476

African (AFR) AF: 0.976 AC: 40573 AN: 41560

American (AMR) AF: 0.924 AC: 14133 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.817 AC: 2833 AN: 3468

East Asian (EAS) AF: 0.904 AC: 4682 AN: 5180

South Asian (SAS) AF: 0.959 AC: 4634 AN: 4834

European-Finnish (FIN) AF: 0.946 AC: 10046 AN: 10614

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.914 AC: 62149 AN: 68030

Other (OTH) AF: 0.891 AC: 1886 AN: 2116

Alfa AF: 0.914 Hom.: 114816

Bravo AF: 0.931

Asia WGS AF: 0.923 AC: 3211 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.49
DANN	Benign	0.39
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

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: rs1681655; hg19: chr3-176792166;