rs1064795585

Variant names:

• chr3-177034322-A-G
• rs1064795585
• NM_024665.7:c.1126T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_024665.7(TBL1XR1):​c.1126T>C​(p.Trp376Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,388,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W376L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TBL1XR1 NM_024665.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.32
• Publications: 2 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: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• Pierpont syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_024665.7
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TBL1XR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 50 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 4.2042 (above the threshold of 3.09). Trascript score misZ: 5.2877 (above the threshold of 3.09). GenCC associations: The gene is linked to complex neurodevelopmental disorder, intellectual disability, autosomal dominant 41, Pierpont syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 3-177034322-A-G is Pathogenic according to our data. Variant chr3-177034322-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 422143.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBL1XR1	NM_024665.7	MANE Select	c.1126T>C	p.Trp376Arg	missense	Exon 13 of 16	NP_078941.2
	TBL1XR1	NM_001321193.3		c.1126T>C	p.Trp376Arg	missense	Exon 13 of 16	NP_001308122.1	Q9BZK7
	TBL1XR1	NM_001321194.3		c.1126T>C	p.Trp376Arg	missense	Exon 14 of 17	NP_001308123.1	Q9BZK7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBL1XR1	ENST00000457928.7	TSL:1 MANE Select	c.1126T>C	p.Trp376Arg	missense	Exon 13 of 16	ENSP00000413251.3	Q9BZK7
	TBL1XR1	ENST00000430069.5	TSL:1	c.1126T>C	p.Trp376Arg	missense	Exon 13 of 16	ENSP00000405574.1	Q9BZK7
	TBL1XR1	ENST00000352800.10	TSL:5	c.1126T>C	p.Trp376Arg	missense	Exon 12 of 15	ENSP00000263964.11	Q9BZK7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1388898 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 688192

African (AFR) AF: 0.00 AC: 0 AN: 29818

American (AMR) AF: 0.00 AC: 0 AN: 27690

Ashkenazi Jewish (ASJ) AF: 0.0000427 AC: 1 AN: 23392

East Asian (EAS) AF: 0.00 AC: 0 AN: 38056

South Asian (SAS) AF: 0.00 AC: 0 AN: 72624

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 51146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4530

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084634

Other (OTH) AF: 0.00 AC: 0 AN: 57008

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		9.3
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.95
MutPred		0.84		Gain of disorder (P = 0.0201)
MVP		0.99
MPC		3.0
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		-0.00090	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.96
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs1064795585; hg19: chr3-176752110; COSMIC: COSV70503816; COSMIC: COSV70503816;