6-108561612-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001455.4(FOXO3):​c.404C>T​(p.Pro135Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000482 in 1,535,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

FOXO3
NM_001455.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.366

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: Likely_benign. The variant received -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.087825984).
BS2
High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FOXO3NM_001455.4 linkc.404C>T p.Pro135Leu 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.404C>T p.Pro135Leu missense_variant Exon 1 of 3 1 NM_001455.4 ENSP00000385824.1 O43524-1
FOXO3ENST00000343882.10 linkc.404C>T p.Pro135Leu missense_variant Exon 2 of 4 1 ENSP00000339527.6 O43524-1

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152046
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000565
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000442
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000730
AC:
9
AN:
123310
AF XY:
0.0000447
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000762
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000470
AC:
65
AN:
1383436
Hom.:
0
Cov.:
32
AF XY:
0.0000469
AC XY:
32
AN XY:
682398
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
30796
American (AMR)
AF:
0.00
AC:
0
AN:
34322
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
23886
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35406
South Asian (SAS)
AF:
0.00
AC:
0
AN:
78508
European-Finnish (FIN)
AF:
0.00110
AC:
50
AN:
45456
Middle Eastern (MID)
AF:
0.000215
AC:
1
AN:
4642
European-Non Finnish (NFE)
AF:
0.0000112
AC:
12
AN:
1073208
Other (OTH)
AF:
0.0000350
AC:
2
AN:
57212
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.510
Heterozygous variant carriers
0
6
12
17
23
29
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
AF:
0.0000592
AC:
9
AN:
152046
Hom.:
0
Cov.:
33
AF XY:
0.0000943
AC XY:
7
AN XY:
74248
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41462
American (AMR)
AF:
0.00
AC:
0
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5162
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.000565
AC:
6
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
312
European-Non Finnish (NFE)
AF:
0.0000442
AC:
3
AN:
67926
Other (OTH)
AF:
0.00
AC:
0
AN:
2080
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.514
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.0000540
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000556
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 24, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.404C>T (p.P135L) alteration is located in exon 1 (coding exon 1) of the FOXO3 gene. This alteration results from a C to T substitution at nucleotide position 404, causing the proline (P) at amino acid position 135 to be replaced by a leucine (L). 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
0.080
BayesDel_addAF
Benign
-0.039
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.42
T;T
Eigen
Benign
-0.79
Eigen_PC
Benign
-0.72
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.60
.;T
M_CAP
Uncertain
0.29
D
MetaRNN
Benign
0.088
T;T
MetaSVM
Benign
-0.85
T
MutationAssessor
Benign
-0.34
N;N
PhyloP100
0.37
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-0.77
N;N
REVEL
Benign
0.24
Sift
Uncertain
0.016
D;D
Sift4G
Benign
0.23
T;T
Polyphen
0.45
B;B
Vest4
0.19
MutPred
0.47
Loss of glycosylation at P135 (P = 0.0022);Loss of glycosylation at P135 (P = 0.0022);
MVP
0.75
ClinPred
0.073
T
GERP RS
1.0
Varity_R
0.051
gMVP
0.36
Mutation Taster
=90/10
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: rs774445254; hg19: chr6-108882815; API