6-108561522-G-A

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

2
4
13

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]

Genome browser will be placed here

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
FOXO3NM_001455.4 linkc.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
FOXO3ENST00000406360.2 linkc.314G>A p.Gly105Glu missense_variant Exon 1 of 3 1 NM_001455.4 ENSP00000385824.1 O43524-1
FOXO3ENST00000343882.10 linkc.314G>A p.Gly105Glu missense_variant Exon 2 of 4 1 ENSP00000339527.6 O43524-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000232
AC:
3
AN:
1292208
Hom.:
0
Cov.:
33
AF XY:
0.00000158
AC XY:
1
AN XY:
631074
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26296
American (AMR)
AF:
0.00
AC:
0
AN:
20650
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
18748
East Asian (EAS)
AF:
0.0000318
AC:
1
AN:
31424
South Asian (SAS)
AF:
0.00
AC:
0
AN:
62960
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
36478
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3642
European-Non Finnish (NFE)
AF:
0.00000193
AC:
2
AN:
1038484
Other (OTH)
AF:
0.00
AC:
0
AN:
53526
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33

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
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.35
T;T
Eigen
Benign
-0.051
Eigen_PC
Benign
-0.0016
FATHMM_MKL
Benign
0.35
N
LIST_S2
Benign
0.57
.;T
M_CAP
Pathogenic
0.84
D
MetaRNN
Benign
0.41
T;T
MetaSVM
Uncertain
-0.20
T
MutationAssessor
Benign
1.7
L;L
PhyloP100
0.39
PrimateAI
Pathogenic
0.90
D
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
T
GERP RS
3.5
Varity_R
0.097
gMVP
0.35
Mutation Taster
=85/15
polymorphism

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

Other links and lift over

dbSNP: rs778713473; hg19: chr6-108882725; API