TLE6

protein-coding

TLE family member 6, subcortical maternal complex member, the group of TLE family|Subcortical maternal complex|WD repeat domain containing

Gene summary

This gene encodes a member of the Groucho/ transducin-like Enhancer of split family of transcriptional co-repressors. The encoded protein is a component of the mammalian subcortical maternal complex, which is required for preimplantation development. In mouse, knock out of this gene results in cleavage-stage embryonic arrest resulting from defective cytoplasmic F-actin meshwork formation and asymmetric cell division. In human, an allelic variant in this gene is associated with preimplantation embryonic lethality. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

MANE transcript

NM_001143986.2

Inheritance

ClinVar variants

P:9U:108B:37

Top phenotype

Oocyte/zygote/embryo maturation arrest 15

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr19:2,977,538-2,995,179

External References & Databases

Ensembl (ENSG00000104953)

Transcript & Mutation Effects

hg38 • Region Span ~17.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

preimplantation embryonic lethality 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014783

Submitter: Labcorp Genetics (formerly Invitae)

preimplantation embryonic lethality 1LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014783

Submitter: Ambry Genetics

preimplantation embryonic lethality 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014783

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Oocyte/zygote/embryo maturation arrest 15AR

Manifestation: Obstetric

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 26537248

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TLE6 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 115

not providedTotal: 26

TLE6-related disorderTotal: 9

Preimplantation embryonic lethality 1Total: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001143986.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	13 clinvar	4 clinvar	20
missense	1 clinvar	1 clinvar	102 clinvar	19 clinvar	1 clinvar	124
nonsense		2 clinvar				2
start loss						0
frameshift	1 clinvar	3 clinvar				4
splice donor/acceptor (+/-2bp)		1 clinvar	3 clinvar			4
Total	2	7	108	32	5	154

Highest pathogenic variant AF is 0.000022923246

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001143986.2	RefSeq	NP_001137458.1	16	MANE Select
ENST00000246112.9	Ensembl	ENSP00000246112.3	16	MANE Select
NM_024760.3	RefSeq	NP_079036.1	11	Standard
ENST00000452088.5	Ensembl	ENSP00000406893.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription, DNA-templated
embryonic process involved in female pregnancy
negative regulation of canonical Wnt signaling pathway
negative regulation of nucleic acid-templated transcription

Molecular Function

transcription corepressor activity
protein binding
repressing transcription factor binding

Cellular Component

nucleus
transcription factor complex
cytoplasm
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000246112
Coding exons: 16
Length: 17734
Individuals with no LoFs: 125684
Homozygous LoFs: 0
Heterozygous LoFs: 63
Defined: 125747
p: 0.000251

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0623	337	340	0.990	0.0000203	3730
Missense (PolyPhen)		87	98.908	0.8796		1105
Synonymous	-2.44	177	140	1.26	0.00000922	1082
Loss of Function	2.99	15	33.7	0.445	0.00000159	356

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00055	0.00055	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00030	0.00030	rare
South Asian	0.00052	0.00052	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: As a member of the subcortical maternal complex (SCMC), plays an essential role for zygotes to progress beyond the first embryonic cell divisions. {ECO:0000269|PubMed:26537248}.;
Disease: DISEASE: Preimplantation embryonic lethality 1 (PREMBL1) [MIM:616814]: A rare cause of female primary infertility. In affected women, ovulation proceeds normally and the retrieved oocytes appear normal, but zygote formation and division are severely impaired. Inheritance is autosomal recessive. {ECO:0000269|PubMed:26537248}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0950

Intolerance Scores

LoFtool: 0.843
RVIS EVS: -1.44
RVIS percentile EVS: 3.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.111

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium