rs77478951

Positions:

• chr3-177038442-G-A
• chr3-177038442-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024665.7(TBL1XR1):​c.926-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0923 in 1,521,326 control chromosomes in the GnomAD database, including 7,592 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 0.070 (597 hom., cov: 32)
  • Exomes 𝑓: 0.095 (6995 hom.)
• Consequence: TBL1XR1 NM_024665.7 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002248
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.09

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-177038442-G-A is Benign according to our data. Variant chr3-177038442-G-A is described in ClinVar as [Benign]. Clinvar id is 448647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBL1XR1	NM_024665.7	c.926-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000457928.7	NP_078941.2
TBL1XR1-AS1	NR_174966.1	n.421G>A		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBL1XR1	ENST00000457928.7	c.926-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_024665.7	ENSP00000413251	P1
TBL1XR1-AS1	ENST00000617758.1	n.421G>A		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.0704 AC: 10708 AN: 152090 Hom.: 597 Cov.: 32

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.0700

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0157

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.0809

GnomAD3 exomes AF: 0.0710 AC: 10806 AN: 152134 Hom.: 525 AF XY: 0.0687 AC XY: 5517 AN XY: 80282

Gnomad AFR exome AF: 0.0158

Gnomad AMR exome AF: 0.0524

Gnomad ASJ exome AF: 0.0289

Gnomad EAS exome AF: 0.000249

Gnomad SAS exome AF: 0.0141

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.0801

GnomAD4 exome AF: 0.0948 AC: 129776 AN: 1369118 Hom.: 6995 Cov.: 31 AF XY: 0.0922 AC XY: 62031 AN XY: 672956

Gnomad4 AFR exome AF: 0.0136

Gnomad4 AMR exome AF: 0.0511

Gnomad4 ASJ exome AF: 0.0317

Gnomad4 EAS exome AF: 0.000134

Gnomad4 SAS exome AF: 0.0141

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.0780

GnomAD4 genome AF: 0.0704 AC: 10709 AN: 152208 Hom.: 597 Cov.: 32 AF XY: 0.0699 AC XY: 5206 AN XY: 74430

Gnomad4 AFR AF: 0.0180

Gnomad4 AMR AF: 0.0700

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0155

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.0796

Alfa AF: 0.0750 Hom.: 197

Bravo AF: 0.0654

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -

Pierpont syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.5
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs77478951; hg19: chr3-176756230;