Genetic Variant FOXO3:p.Gly105Glu (chr6-108561522-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001455.4(FOXO3):c.314G>A(p.Gly105Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000232 in 1,292,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

FOXO3
NM_001455.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.387

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40727186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO3	NM_001455.4 link	c.314G>A	p.Gly105Glu	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.314G>A	p.Gly105Glu	missense_variant	Exon 1 of 3	1	NM_001455.4	ENSP00000385824.1		O43524-1
FOXO3	ENST00000343882.10 link	c.314G>A	p.Gly105Glu	missense_variant	Exon 2 of 4	1		ENSP00000339527.6		O43524-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000232

AC:

AN:

1292208

Hom.:

Cov.:

AF XY:

0.00000158

AC XY:

AN XY:

631074

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26296

American (AMR)

AF:

0.00

AC:

AN:

20650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18748

East Asian (EAS)

AF:

0.0000318

AC:

AN:

31424

South Asian (SAS)

AF:

0.00

AC:

AN:

62960

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3642

European-Non Finnish (NFE)

AF:

0.00000193

AC:

AN:

1038484

Other (OTH)

AF:

0.00

AC:

AN:

53526

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 18, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.314G>A (p.G105E) alteration is located in exon 1 (coding exon 1) of the FOXO3 gene. This alteration results from a G to A substitution at nucleotide position 314, causing the glycine (G) at amino acid position 105 to be replaced by a glutamic acid (E). 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

0.094

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

T;T

Eigen

Benign

-0.051

Eigen_PC

Benign

-0.0016

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.57

.;T

M_CAP

Pathogenic

0.84

MetaRNN

Benign

0.41

T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.7

L;L

PhyloP100

0.39

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

0.33

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.13

T;T

Sift4G

Benign

0.80

T;T

Polyphen

0.57

P;P

Vest4

0.31

MutPred

0.19

Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);

MVP

0.88

ClinPred

0.37

GERP RS

3.5

Varity_R

0.097

gMVP

0.35

Mutation Taster

=85/15

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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6-108561522-G-A

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