19-2993574-C-A

Variant names:

• chr19-2993574-C-A
• rs767222404
• NM_001143986.2:c.1529C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_001143986.2(TLE6):​c.1529C>A​(p.Ser510Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000709 in 1,410,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TLE6 NM_001143986.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.67
• Publications: 12 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795
• PP5: Variant 19-2993574-C-A is Pathogenic according to our data. 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.

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.1529C>A	p.Ser510Tyr	missense	Exon 15 of 17	NP_001137458.1
	TLE6	NM_024760.3		c.1160C>A	p.Ser387Tyr	missense	Exon 14 of 16	NP_079036.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLE6	ENST00000246112.9	TSL:1 MANE Select	c.1529C>A	p.Ser510Tyr	missense	Exon 15 of 17	ENSP00000246112.3
	TLE6	ENST00000452088.5	TSL:1	c.1160C>A	p.Ser387Tyr	missense	Exon 14 of 16	ENSP00000406893.1
	TLE6	ENST00000958788.1		c.1529C>A	p.Ser510Tyr	missense	Exon 15 of 17	ENSP00000628847.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410174 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 694022

African (AFR) AF: 0.00 AC: 0 AN: 31754

American (AMR) AF: 0.00 AC: 0 AN: 38662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23944

East Asian (EAS) AF: 0.00 AC: 0 AN: 38444

South Asian (SAS) AF: 0.00 AC: 0 AN: 81314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52426

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5496

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080166

Other (OTH) AF: 0.00 AC: 0 AN: 57968

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Preimplantation embryonic lethality 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.7
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Vest4		0.72
MVP		0.54
MPC		0.25
ClinPred		0.98	D
GERP RS		3.4
Varity_R		0.45
gMVP		0.46
Mutation Taster		=38/62	disease causing (ClinVar)

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: rs767222404; hg19: chr19-2993572;