19-2978251-G-T

Variant names:

• chr19-2978251-G-T
• rs190951421
• NM_001143986.2:c.18G>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001143986.2(TLE6):​c.18G>T​(p.Gln6His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000393 in 1,551,494 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: TLE6 NM_001143986.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.264

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003497243).
• BP6: Variant 19-2978251-G-T is Benign according to our data. Variant chr19-2978251-G-T is described in ClinVar as [Benign]. Clinvar id is 3050493.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00198 (302/152224) while in subpopulation AFR AF= 0.00708 (294/41554). AF 95% confidence interval is 0.00641. There are 1 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLE6	NM_001143986.2	c.18G>T	p.Gln6His	missense_variant	Exon 2 of 17	ENST00000246112.9	NP_001137458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLE6	ENST00000246112.9	c.18G>T	p.Gln6His	missense_variant	Exon 2 of 17	1	NM_001143986.2	ENSP00000246112.3

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 302 AN: 152106 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00710

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000500 AC: 78 AN: 156044 Hom.: 1 AF XY: 0.000435 AC XY: 36 AN XY: 82782

Gnomad AFR exome AF: 0.00835

Gnomad AMR exome AF: 0.000486

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000220 AC: 308 AN: 1399270 Hom.: 1 Cov.: 31 AF XY: 0.000183 AC XY: 126 AN XY: 690136

Gnomad4 AFR exome AF: 0.00823

Gnomad4 AMR exome AF: 0.000392

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000569

GnomAD4 genome AF: 0.00198 AC: 302 AN: 152224 Hom.: 1 Cov.: 31 AF XY: 0.00200 AC XY: 149 AN XY: 74438

Gnomad4 AFR AF: 0.00708

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00152 Hom.: 0

Bravo AF: 0.00235

ExAC AF: 0.000879 AC: 22

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TLE6-related disorder Benign:1

Jul 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.26
DANN	Benign	0.94
DEOGEN2	Benign	0.023	T;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.33	T;T;T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.54	N;N;.
REVEL	Benign	0.10
Sift	Uncertain	0.0060	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.066
MutPred		0.054		Loss of MoRF binding (P = 0.1013);Loss of MoRF binding (P = 0.1013);Loss of MoRF binding (P = 0.1013);
MVP		0.014
MPC		0.061
ClinPred		0.0053	T
GERP RS		-3.6
Varity_R		0.066
gMVP		0.084

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

Publications

LitVar

Other links and lift over

dbSNP: rs190951421; hg19: chr19-2978249;