3-177047481-T-C

Variant names:

• chr3-177047481-T-C
• rs3749234
• NM_024665.7:c.766+5A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024665.7(TBL1XR1):​c.766+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,611,488 control chromosomes in the GnomAD database, including 35,897 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (3099 hom., cov: 32)
  • Exomes 𝑓: 0.20 (32798 hom.)
• Consequence: TBL1XR1 NM_024665.7 splice_region, intron
• Scores: Splicing: ADA: 0.00008531
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.276
• Publications: 14 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-AS1 (HGNC:41243): (TBL1XR1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 3-177047481-T-C is Benign according to our data. Variant chr3-177047481-T-C is described in ClinVar as Benign. ClinVar VariationId is 586783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.482 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.766+5A>G		splice_region intron	N/A	NP_078941.2
	TBL1XR1	NM_001321193.3		c.766+5A>G		splice_region intron	N/A	NP_001308122.1
	TBL1XR1	NM_001321194.3		c.766+5A>G		splice_region 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.766+5A>G		splice_region intron	N/A	ENSP00000413251.3
	TBL1XR1	ENST00000430069.5	TSL:1	c.766+5A>G		splice_region intron	N/A	ENSP00000405574.1
	TBL1XR1	ENST00000352800.10	TSL:5	c.766+5A>G		splice_region intron	N/A	ENSP00000263964.11

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26343 AN: 152074 Hom.: 3093 Cov.: 32

Gnomad AFR AF: 0.0506

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.0803

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.173

GnomAD2 exomes AF: 0.211 AC: 52232 AN: 247644 AF XY: 0.203

Gnomad AFR exome AF: 0.0468

Gnomad AMR exome AF: 0.225

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.520

Gnomad FIN exome AF: 0.257

Gnomad NFE exome AF: 0.211

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.202 AC: 294498 AN: 1459296 Hom.: 32798 Cov.: 32 AF XY: 0.198 AC XY: 143739 AN XY: 725936

African (AFR) AF: 0.0423 AC: 1414 AN: 33404

American (AMR) AF: 0.222 AC: 9885 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 4407 AN: 26062

East Asian (EAS) AF: 0.457 AC: 18114 AN: 39620

South Asian (SAS) AF: 0.0791 AC: 6806 AN: 86008

European-Finnish (FIN) AF: 0.253 AC: 13500 AN: 53340

Middle Eastern (MID) AF: 0.149 AC: 848 AN: 5706

European-Non Finnish (NFE) AF: 0.205 AC: 227768 AN: 1110316

Other (OTH) AF: 0.195 AC: 11756 AN: 60258

GnomAD4 genome AF: 0.173 AC: 26355 AN: 152192 Hom.: 3099 Cov.: 32 AF XY: 0.178 AC XY: 13233 AN XY: 74400

African (AFR) AF: 0.0505 AC: 2098 AN: 41562

American (AMR) AF: 0.218 AC: 3331 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 599 AN: 3466

East Asian (EAS) AF: 0.498 AC: 2577 AN: 5178

South Asian (SAS) AF: 0.0798 AC: 384 AN: 4814

European-Finnish (FIN) AF: 0.247 AC: 2612 AN: 10582

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14092 AN: 67986

Other (OTH) AF: 0.179 AC: 379 AN: 2116

Alfa AF: 0.190 Hom.: 8466

Bravo AF: 0.170

Asia WGS AF: 0.222 AC: 769 AN: 3476

EpiCase AF: 0.205

EpiControl AF: 0.204

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Jan 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Pierpont syndrome Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.4
DANN	Benign	0.77
PhyloP100		-0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=62/38	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000085
dbscSNV1_RF	Benign	0.0060
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: rs3749234; hg19: chr3-176765269; COSMIC: COSV61789436; COSMIC: COSV61789436;