rs1553810244

Variant names:

• chr3-177038369-T-A
• rs1553810244
• NM_024665.7:c.991A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_024665.7(TBL1XR1):​c.991A>T​(p.Ile331Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBL1XR1 NM_024665.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.99
• Publications: 0 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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, 0.896
• PP5: Variant 3-177038369-T-A is Pathogenic according to our data. Variant chr3-177038369-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521292.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBL1XR1	NM_024665.7	c.991A>T	p.Ile331Phe	missense_variant	Exon 11 of 16	ENST00000457928.7	NP_078941.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL1XR1	ENST00000457928.7	c.991A>T	p.Ile331Phe	missense_variant	Exon 11 of 16	1	NM_024665.7	ENSP00000413251.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Sep 22, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.1	M;M
PhyloP100		8.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.99	D;D
Vest4		0.85
MutPred		0.59		Loss of catalytic residue at L336 (P = 0.0219);Loss of catalytic residue at L336 (P = 0.0219);
MVP		0.95
MPC		2.8
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.86
gMVP		0.77
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: rs1553810244; hg19: chr3-176756157; COSMIC: COSV70500636; COSMIC: COSV70500636;