Genetic Variant TLE6:p.Ser510Cys (chr19-2993574-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_001143986.2(TLE6):c.1529C>G(p.Ser510Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000142 in 1,410,174 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S510Y) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TLE6
NM_001143986.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.67

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

preimplantation embryonic lethality 1
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

TLE6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-2993574-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 222026.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLE6	NM_001143986.2 link	c.1529C>G	p.Ser510Cys	missense_variant	Exon 15 of 17	ENST00000246112.9	NP_001137458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TLE6	ENST00000246112.9 link	c.1529C>G	p.Ser510Cys	missense_variant	Exon 15 of 17	1	NM_001143986.2	ENSP00000246112.3
TLE6	ENST00000452088.5 link	c.1160C>G	p.Ser387Cys	missense_variant	Exon 14 of 16	1		ENSP00000406893.1
TLE6	ENST00000497878.5 link	n.1222C>G		non_coding_transcript_exon_variant	Exon 6 of 8	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000892

AC:

AN:

224144

AF XY:

0.00000826

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1410174

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

694022

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31754

American (AMR)

AF:

0.00

AC:

AN:

38662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23944

East Asian (EAS)

AF:

0.00

AC:

AN:

38444

South Asian (SAS)

AF:

0.00

AC:

AN:

81314

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52426

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5496

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1080166

Other (OTH)

AF:

0.00

AC:

AN:

57968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.0064

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.71

D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

3.7

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.8

D;D

REVEL

Benign

0.20

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0080

D;D

Vest4

0.61

ClinPred

0.92

GERP RS

3.4

Varity_R

0.25

gMVP

0.38

Mutation Taster

=57/43

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over