chr19-3000657-C-A

Variant names:

• chr19-3000657-C-A
• rs143713547
• NM_003260.5:c.2114G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S705N) has been classified as Likely benign.

• 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
• Publications: 0 publications found

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

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003260.5. 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
	TLE2	NM_003260.5	MANE Select	c.2114G>T	p.Ser705Ile	missense	Exon 19 of 20	NP_003251.2
	TLE2	NM_001300846.2		c.2117G>T	p.Ser706Ile	missense	Exon 19 of 20	NP_001287775.1	K7EMK7
	TLE2	NM_001144762.2		c.1748G>T	p.Ser583Ile	missense	Exon 17 of 18	NP_001138234.1	Q04725-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLE2	ENST00000262953.11	TSL:1 MANE Select	c.2114G>T	p.Ser705Ile	missense	Exon 19 of 20	ENSP00000262953.5	Q04725-1
	TLE2	ENST00000590536.5	TSL:1	c.2117G>T	p.Ser706Ile	missense	Exon 19 of 20	ENSP00000466542.1	K7EMK7
	TLE2	ENST00000591529.5	TSL:1	c.2089+1696G>T		intron	N/A	ENSP00000468279.1	Q04725-3

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

African (AFR) AF: 0.00 AC: 0 AN: 32810

American (AMR) AF: 0.00 AC: 0 AN: 40864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25640

East Asian (EAS) AF: 0.00 AC: 0 AN: 38252

South Asian (SAS) AF: 0.00 AC: 0 AN: 82040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5644

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1099496

Other (OTH) AF: 0.00 AC: 0 AN: 59488

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	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
Mutation Taster		=67/33	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: rs143713547; hg19: chr19-3000655;