rs776453307

Positions:

• chr19-2989673-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001143986.2(TLE6):​c.1133del​(p.Ala378GlufsTer75) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: TLE6 NM_001143986.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0370

Genes affected

TLE6 (HGNC:30788): (TLE family member 6, subcortical maternal complex member) 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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-2989673-GC-G is Pathogenic according to our data. Variant chr19-2989673-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 453260.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLE6	NM_001143986.2	c.1133del	p.Ala378GlufsTer75	frameshift_variant	13/17	ENST00000246112.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLE6	ENST00000246112.9	c.1133del	p.Ala378GlufsTer75	frameshift_variant	13/17	1	NM_001143986.2	A2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251088 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135742

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461856 Hom.: 0 Cov.: 33 AF XY: 0.0000261 AC XY: 19 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Preimplantation embryonic lethality 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Laboratory, Nadiya Clinic of Reproductive Medicine

Dec 11, 2017

The deletion NM_001143986.1(TLE6):c.1133delC (p.(Ala378GlufsTer463)) results in a frameshift. The frameshift changes C-terminal sequence of TLE6 protein and creates adjacent premature stop codons at positions 463 and 464 of the new reading frame. Thus, translation of the altered mRNA is predicted to result in the formation of a protein lacking the WD3 and WD4 repeat motifs (due to change in amino acid sequence) and WD5, WD6 and WD7 repeat motifs (due to the introduction of terminating codons). The aforementioned repeat motifs are a part of a highly conservative WD40 repeat domain that is critical for protein function. (PMID:18254933, 12057191) This variant is rare. It has been observed with 0.00007182 frequency in the European (Non-Finnish) population, 0.00006534 frequency in the African population and has not been observed in other populations in gnomAD Exomes (ExAC). The site corresponding to the variant has mean coverage of 77 and median coverage of 82 in gnomAD samples, 98.82% of samples have coverage over 20x. A pathogenic variant TLE6:c.1529C>A (p.Ser510Tyr) in the homozygous state that results in losing a canonical phosphorylation site for PKA and reduced binding to components of the subcortical maternal complex has been observed in 3 women with primary infertility due to preimplantation embryonic lethality 1 (PREMBL1) (PMID: 26537248). Therefore, we consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs776453307; hg19: chr19-2989671;