Genetic Variant FOXO3:p.Leu18Val (chr6-108561260-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001455.4(FOXO3):c.52C>G(p.Leu18Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,413,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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

FOXO3
NM_001455.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.24

Publications

0 publications found

Variant links:

Genes affected

FOXO3 (HGNC:3821): (forkhead box O3) This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. This gene likely functions as a trigger for apoptosis through expression of genes necessary for cell death. Translocation of this gene with the MLL gene is associated with secondary acute leukemia. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]

FOXO3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23312673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO3	NM_001455.4 link	c.52C>G	p.Leu18Val	missense_variant	Exon 1 of 3	ENST00000406360.2	NP_001446.1	O43524-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXO3	ENST00000406360.2 link	c.52C>G	p.Leu18Val	missense_variant	Exon 1 of 3	1	NM_001455.4	ENSP00000385824.1		O43524-1
FOXO3	ENST00000343882.10 link	c.52C>G	p.Leu18Val	missense_variant	Exon 2 of 4	1		ENSP00000339527.6		O43524-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1413108

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699186

show subpopulations

African (AFR)

AF:

0.0000628

AC:

AN:

31858

American (AMR)

AF:

0.00

AC:

AN:

37762

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25194

East Asian (EAS)

AF:

0.00

AC:

AN:

36764

South Asian (SAS)

AF:

0.00

AC:

AN:

80680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4086

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1089908

Other (OTH)

AF:

0.00

AC:

AN:

58492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 29, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.52C>G (p.L18V) alteration is located in exon 1 (coding exon 1) of the FOXO3 gene. This alteration results from a C to G substitution at nucleotide position 52, causing the leucine (L) at amino acid position 18 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

Benign

0.067

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.31

T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.75

.;T

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.4

L;L

PhyloP100

1.2

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

0.35

N;N

REVEL

Benign

0.18

Sift

Benign

0.034

D;D

Sift4G

Benign

0.14

T;T

Polyphen

0.022

B;B

Vest4

0.031

MutPred

0.29

Loss of stability (P = 0.0569);Loss of stability (P = 0.0569);

MVP

0.71

ClinPred

0.25

GERP RS

2.2

PromoterAI

-0.028

Neutral

(source)

Varity_R

0.11

gMVP

0.20

Mutation Taster

=77/23

polymorphism

(source)

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

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6-108561260-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over