19-3053896-C-T

Variant names:

• chr19-3053896-C-T
• rs1599266959
• NM_001130.6:c.517G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001130.6(TLE5):​c.517G>A​(p.Ala173Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TLE5 NM_001130.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

Genes affected

TLE5 (HGNC:307): (TLE family member 5, transcriptional modulator) The protein encoded by this gene is similar in sequence to the amino terminus of Drosophila enhancer of split groucho, a protein involved in neurogenesis during embryonic development. The encoded protein, which belongs to the groucho/TLE family of proteins, can function as a homooligomer or as a heteroologimer with other family members to dominantly repress the expression of other family member genes. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ENSG00000267469 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12956873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLE5	NM_001130.6	c.517G>A	p.Ala173Thr	missense_variant	Exon 7 of 7	ENST00000327141.9	NP_001121.2
TLE5	NM_198969.1	c.718G>A	p.Ala240Thr	missense_variant	Exon 7 of 7		NP_945320.1
TLE5	NM_198970.2	c.514G>A	p.Ala172Thr	missense_variant	Exon 7 of 7		NP_945321.1
TLE5	XM_006722664.2	c.715G>A	p.Ala239Thr	missense_variant	Exon 7 of 7		XP_006722727.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLE5	ENST00000327141.9	c.517G>A	p.Ala173Thr	missense_variant	Exon 7 of 7	1	NM_001130.6	ENSP00000317537.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460908 Hom.: 0 Cov.: 41 AF XY: 0.00000138 AC XY: 1 AN XY: 726758

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.718G>A (p.A240T) alteration is located in exon 7 (coding exon 7) of the AES gene. This alteration results from a G to A substitution at nucleotide position 718, causing the alanine (A) at amino acid position 240 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	.;T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;L;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.7	N;N;.
REVEL	Benign	0.10
Sift	Benign	0.083	T;T;.
Sift4G	Benign	0.061	T;T;T
Polyphen		0.0010	.;B;.
Vest4		0.085
MutPred		0.051		.;Gain of methylation at K177 (P = 0.0615);.;
MVP		0.31
MPC		0.35
ClinPred		0.77	D
GERP RS		1.4
Varity_R		0.044
gMVP		0.52

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: rs1599266959; hg19: chr19-3053894;