19-2993574-C-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

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 Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TLE6 NM_001143986.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.67

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a modified_residue Phosphoserine; by PKA (size 0) in uniprot entity TLE6_HUMAN
• 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 Lovd as [Pathogenic].

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000892 AC: 2 AN: 224144 Hom.: 0 AF XY: 0.00000826 AC XY: 1 AN XY: 121100

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 SAS 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: 2 AN: 1410174 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 694022

Gnomad4 AFR exome AF: 0.00

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: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

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	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Benign	0.34	T
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
MVP		0.62
MPC		0.24
ClinPred		0.92	D
GERP RS		3.4
Varity_R		0.25
gMVP		0.38

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: rs767222404; hg19: chr19-2993572; COSMIC: COSV53580365; COSMIC: COSV53580365;