19-3056327-G-C

Variant names:

• chr19-3056327-G-C
• rs1401494957
• NM_001130.6:c.219C>G

Variant summary

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

The NM_001130.6(TLE5):​c.219C>G​(p.Ile73Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,334,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TLE5 NM_001130.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.730

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 rank	MANE	Protein	UniProt
TLE5	NM_001130.6	c.219C>G	p.Ile73Met	missense_variant	Exon 4 of 7	ENST00000327141.9	NP_001121.2
TLE5	NM_198969.1	c.420C>G	p.Ile140Met	missense_variant	Exon 4 of 7		NP_945320.1
TLE5	NM_198970.2	c.219C>G	p.Ile73Met	missense_variant	Exon 4 of 7		NP_945321.1
TLE5	XM_006722664.2	c.420C>G	p.Ile140Met	missense_variant	Exon 4 of 7		XP_006722727.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLE5	ENST00000327141.9	c.219C>G	p.Ile73Met	missense_variant	Exon 4 of 7	1	NM_001130.6	ENSP00000317537.4

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1334026 Hom.: 0 Cov.: 33 AF XY: 0.00000304 AC XY: 2 AN XY: 657448

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000339

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.62e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.420C>G (p.I140M) alteration is located in exon 4 (coding exon 4) of the AES gene. This alteration results from a C to G substitution at nucleotide position 420, causing the isoleucine (I) at amino acid position 140 to be replaced by a methionine (M). 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	Uncertain	0.50
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	7.0
DANN	Benign	0.91
DEOGEN2	Uncertain	0.62	.;D;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.2	.;L;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.8	D;D;.
REVEL	Benign	0.22
Sift	Uncertain	0.018	D;D;.
Sift4G	Benign	0.064	T;T;T
Polyphen		0.041	.;B;.
Vest4		0.67
MutPred		0.63		.;Gain of disorder (P = 0.0614);.;
MVP		0.55
MPC		2.1
ClinPred		0.86	D
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.88

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: rs1401494957; hg19: chr19-3056325;