rs61750379

chr3-177051640-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_024665.7(TBL1XR1):c.291A>G(p.Gln97=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 1,613,684 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0071 (63 hom.)
• Consequence: TBL1XR1 NM_024665.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.57

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 3-177051640-T-C is Benign according to our data. Variant chr3-177051640-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 468535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.57 with no splicing effect.
• BS2: High AC in GnomAd at 645 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBL1XR1	NM_024665.7	c.291A>G	p.Gln97=	synonymous_variant	5/16	ENST00000457928.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBL1XR1	ENST00000457928.7	c.291A>G	p.Gln97=	synonymous_variant	5/16	1	NM_024665.7	P1

Frequencies

GnomAD3 genomes AF: 0.00424 AC: 645 AN: 151974 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00776

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00724

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00446 AC: 1110 AN: 248688 Hom.: 6 AF XY: 0.00420 AC XY: 567 AN XY: 134910

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.000899

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00938

Gnomad NFE exome AF: 0.00732

Gnomad OTH exome AF: 0.00447

GnomAD4 exome AF: 0.00706 AC: 10319 AN: 1461592 Hom.: 63 Cov.: 31 AF XY: 0.00683 AC XY: 4964 AN XY: 727074

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0109

Gnomad4 NFE exome AF: 0.00840

Gnomad4 OTH exome AF: 0.00495

GnomAD4 genome AF: 0.00424 AC: 645 AN: 152092 Hom.: 0 Cov.: 31 AF XY: 0.00420 AC XY: 312 AN XY: 74358

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00776

Gnomad4 NFE AF: 0.00724

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00592 Hom.: 1

Bravo AF: 0.00385

EpiCase AF: 0.00607

EpiControl AF: 0.00593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	TBL1XR1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2018	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2016

This alteration is classified as likely 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	7.7
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs61750379; hg19: chr3-176769428;