3-177038114-T-C

Position:

• chr3-177038114-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_024665.7(TBL1XR1):​c.1106A>G​(p.Asp369Gly) 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: 7.94

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TBL1XR1. . Gene score misZ: 4.2042 (greater than the threshold 3.09). Trascript score misZ: 5.2877 (greater than threshold 3.09). The gene has 50 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. GenCC has associacion of the gene with Pierpont syndrome, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 41.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• PP5: Variant 3-177038114-T-C is Pathogenic according to our data. Variant chr3-177038114-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2627906.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBL1XR1	NM_024665.7	c.1106A>G	p.Asp369Gly	missense_variant	12/16	ENST00000457928.7	NP_078941.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBL1XR1	ENST00000457928.7	c.1106A>G	p.Asp369Gly	missense_variant	12/16	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

TBL1XR1-related neurodevelopmental disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 04, 2023

The TBL1XR1 c.1106A>G (p.Asp369Gly) missense variant has not, to our knowledge, been reported in the peer-reviewed literature. However, another variant at the same amino acid position, c.1107C>A (p.Asp369Gly), classified as a variant of uncertain significance, has been reported in a heterozygous de novo state in an individual with a developmental disorder (PMID:31785789). The c.1106A>G variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The c.1106A>G variant is located in a known mutational hotspot (PMID: 32524419) with multiple lines of computational evidence suggesting the variant may impact the gene or gene product. This variant was identified in a de novo state. Based on the available evidence, the c.1106A>G (p.Asp369Gly) variant is classified as likely pathogenic for TBL1XR1-related neurodevelopmental disorder. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.68	N;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.046	D;D
Polyphen		0.99	D;D
Vest4		0.87
MutPred		0.59		Loss of stability (P = 0.0294);Loss of stability (P = 0.0294);
MVP		0.91
MPC		2.6
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-176755902; COSMIC: COSV70499473; COSMIC: COSV70499473;