chr19-3056347-T-C

Position:

• chr19-3056347-T-C

Variant summary

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

The ENST00000327141.9(TLE5):​c.199A>G​(p.Met67Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 19)
• Consequence: TLE5 ENST00000327141.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLE5	NM_001130.6	c.199A>G	p.Met67Val	missense_variant	4/7	ENST00000327141.9	NP_001121.2
TLE5	NM_198969.1	c.400A>G	p.Met134Val	missense_variant	4/7		NP_945320.1
TLE5	NM_198970.2	c.199A>G	p.Met67Val	missense_variant	4/7		NP_945321.1
TLE5	XM_006722664.2	c.400A>G	p.Met134Val	missense_variant	4/7		XP_006722727.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLE5	ENST00000327141.9	c.199A>G	p.Met67Val	missense_variant	4/7	1	NM_001130.6	ENSP00000317537	P1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 19

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The c.400A>G (p.M134V) alteration is located in exon 4 (coding exon 4) of the AES gene. This alteration results from a A to G substitution at nucleotide position 400, causing the methionine (M) at amino acid position 134 to be replaced by a valine (V). 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Uncertain	0.77	.;D;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.040
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;T;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.4	.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D;D;.
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.0050	.;B;.
Vest4		0.62
MutPred		0.78		.;Gain of phosphorylation at Y69 (P = 0.1691);.;
MVP		0.74
MPC		1.6
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.88
gMVP		0.94

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: rs1359111053; hg19: chr19-3056345;