19-3000657-C-A

Variant names:

• chr19-3000657-C-A
• NM_003260.5:c.2114G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003260.5(TLE2):​c.2114G>T​(p.Ser705Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,435,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TLE2 NM_003260.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.84

Genes affected

TLE2 (HGNC:11838): (TLE family member 2, transcriptional corepressor) Enables transcription corepressor activity. Involved in negative regulation of canonical Wnt signaling pathway and negative regulation of transcription, DNA-templated. Located in focal adhesion and nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLE2	NM_003260.5	c.2114G>T	p.Ser705Ile	missense_variant	Exon 19 of 20	ENST00000262953.11	NP_003251.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLE2	ENST00000262953.11	c.2114G>T	p.Ser705Ile	missense_variant	Exon 19 of 20	1	NM_003260.5	ENSP00000262953.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1435630 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 711584

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: 0.00000273

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.0	D;D;D;.
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.82
MutPred		0.42		Loss of disorder (P = 0.0182);.;.;.;
MVP		0.67
MPC		1.7
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.89
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-3000655;