3-177038442-G-A

Variant names:

• chr3-177038442-G-A
• rs77478951
• NM_024665.7:c.926-8C>T

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.926-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0923 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, intron
• Scores: Splicing: ADA: 0.00002248
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.09
• 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-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=-0.83).
• BP6: Variant 3-177038442-G-A is Benign according to our data. Variant chr3-177038442-G-A is described in ClinVar as Benign. ClinVar VariationId 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.

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.926-8C>T		splice_region intron	N/A	NP_078941.2
	TBL1XR1-AS1	NR_174966.1		n.421G>A		non_coding_transcript_exon	Exon 2 of 4
	TBL1XR1	NM_001321193.3		c.926-8C>T		splice_region intron	N/A	NP_001308122.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBL1XR1	ENST00000457928.7	TSL:1 MANE Select	c.926-8C>T		splice_region intron	N/A	ENSP00000413251.3
	TBL1XR1	ENST00000430069.5	TSL:1	c.926-8C>T		splice_region intron	N/A	ENSP00000405574.1
	TBL1XR1-AS1	ENST00000617758.2	TSL:5	n.421G>A		non_coding_transcript_exon	Exon 2 of 4

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

GnomAD2 exomes AF: 0.0710 AC: 10806 AN: 152134 AF XY: 0.0687

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 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

African (AFR) AF: 0.0136 AC: 419 AN: 30894

American (AMR) AF: 0.0511 AC: 1549 AN: 30304

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 731 AN: 23070

East Asian (EAS) AF: 0.000134 AC: 5 AN: 37274

South Asian (SAS) AF: 0.0141 AC: 1019 AN: 72486

European-Finnish (FIN) AF: 0.113 AC: 5484 AN: 48714

Middle Eastern (MID) AF: 0.0148 AC: 81 AN: 5458

European-Non Finnish (NFE) AF: 0.109 AC: 116079 AN: 1064384

Other (OTH) AF: 0.0780 AC: 4409 AN: 56534

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

African (AFR) AF: 0.0180 AC: 746 AN: 41542

American (AMR) AF: 0.0700 AC: 1072 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0155 AC: 75 AN: 4828

European-Finnish (FIN) AF: 0.107 AC: 1137 AN: 10582

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7261 AN: 67984

Other (OTH) AF: 0.0796 AC: 168 AN: 2110

Alfa AF: 0.0747 Hom.: 409

Bravo AF: 0.0654

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Pierpont syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.5
DANN	Benign	0.58
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs77478951; hg19: chr3-176756230;