NM_001143986.2:c.386C>G

Variant names:

• chr19-2987083-C-G
• rs371606064
• NM_001143986.2:c.386C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001143986.2(TLE6):​c.386C>G​(p.Ser129Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. S129Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLE6 NM_001143986.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.902
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15888661).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143986.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLE6	NM_001143986.2	MANE Select	c.386C>G	p.Ser129Cys	missense	Exon 7 of 17	NP_001137458.1	Q9H808-1
	TLE6	NM_024760.3		c.17C>G	p.Ser6Cys	missense	Exon 6 of 16	NP_079036.1	Q9H808-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLE6	ENST00000246112.9	TSL:1 MANE Select	c.386C>G	p.Ser129Cys	missense	Exon 7 of 17	ENSP00000246112.3	Q9H808-1
	TLE6	ENST00000452088.5	TSL:1	c.17C>G	p.Ser6Cys	missense	Exon 6 of 16	ENSP00000406893.1	Q9H808-2
	TLE6	ENST00000958788.1		c.386C>G	p.Ser129Cys	missense	Exon 7 of 17	ENSP00000628847.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.90
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.097
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0080	D
Vest4		0.29
MVP		0.66
MPC		0.38
ClinPred		0.42	T
GERP RS		2.8
Varity_R		0.13
gMVP		0.23
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs371606064; hg19: chr19-2987081;