19-2982152-A-G

Position:

chr19-2982152-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001143986.2(TLE6):c.185A>G(p.His62Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000767 in 1,551,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

TLE6
NM_001143986.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0210

Variant links:

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]

TLE6 links:

TLE6 (HGNC:):

TLE6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.00916788).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000486 (74/152184) while in subpopulation AFR AF= 0.00178 (74/41526). AF 95% confidence interval is 0.00146. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLE6	NM_001143986.2 linkuse as main transcript	c.185A>G	p.His62Arg	missense_variant	5/17	ENST00000246112.9	NP_001137458.1	Q9H808-1
TLE6	XM_005259645.3 linkuse as main transcript	c.185A>G	p.His62Arg	missense_variant	5/17		XP_005259702.1	Q9H808-1
TLE6	XM_011528300.3 linkuse as main transcript	c.185A>G	p.His62Arg	missense_variant	5/17		XP_011526602.1	Q9H808-1
TLE6	NM_024760.3 linkuse as main transcript	c.-185A>G		5_prime_UTR_variant	4/16		NP_079036.1	Q9H808-2Q6PJM9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TLE6	ENST00000246112.9 linkuse as main transcript	c.185A>G	p.His62Arg	missense_variant	5/17	1	NM_001143986.2	ENSP00000246112.3	Q9H808-1
TLE6	ENST00000452088 linkuse as main transcript	c.-185A>G		5_prime_UTR_variant	4/16	1		ENSP00000406893.1	Q9H808-2
TLE6	ENST00000453329.5 linkuse as main transcript	c.185A>G	p.His62Arg	missense_variant	5/7	4		ENSP00000411783.1	C9J532
TLE6	ENST00000468176.7 linkuse as main transcript	n.268A>G		non_coding_transcript_exon_variant	5/10	5

Frequencies

GnomAD3 genomes

AF:

0.000487

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000454

AC:

AN:

154106

Hom.:

AF XY:

0.0000367

AC XY:

AN XY:

81764

show subpopulations

Gnomad AFR exome

AF:

0.000884

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1399376

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

690198

show subpopulations

Gnomad4 AFR exome

AF:

0.00127

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:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000690

GnomAD4 genome

AF:

0.000486

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00178

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000515

Hom.:

Bravo

AF:

0.000536

ESP6500AA

AF:

0.00217

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000158

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2023

The c.185A>G (p.H62R) alteration is located in exon 5 (coding exon 4) of the TLE6 gene. This alteration results from a A to G substitution at nucleotide position 185, causing the histidine (H) at amino acid position 62 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.2

DANN

Benign

0.70

DEOGEN2

Benign

0.034

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.36

T;T

M_CAP

Benign

0.0018

MetaRNN

Benign

0.0092

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.55

N;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.79

N;D

REVEL

Benign

0.014

Sift

Uncertain

0.024

D;T

Sift4G

Benign

0.16

T;D

Vest4

0.072

MVP

0.39

MPC

0.077

ClinPred

0.017

GERP RS

0.24

Varity_R

0.13

gMVP

0.034

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over