6-108561621-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001455.4(FOXO3):​c.413C>T​(p.Pro138Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.0023 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00018 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

FOXO3
NM_001455.4 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.249

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 -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.122706205).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FOXO3NM_001455.4 linkc.413C>T p.Pro138Leu 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.413C>T p.Pro138Leu missense_variant Exon 1 of 3 1 NM_001455.4 ENSP00000385824.1 O43524-1
FOXO3ENST00000343882.10 linkc.413C>T p.Pro138Leu missense_variant Exon 2 of 4 1 ENSP00000339527.6 O43524-1

Frequencies

GnomAD3 genomes
AF:
0.00230
AC:
344
AN:
149474
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00804
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00105
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000415
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00147
GnomAD2 exomes
AF:
0.0000788
AC:
11
AN:
139624
AF XY:
0.0000916
show subpopulations
Gnomad AFR exome
AF:
0.00130
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000258
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.000176
AC:
246
AN:
1395578
Hom.:
0
Cov.:
32
AF XY:
0.000139
AC XY:
96
AN XY:
689784
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00523
AC:
155
AN:
29664
American (AMR)
AF:
0.0000557
AC:
2
AN:
35904
Ashkenazi Jewish (ASJ)
AF:
0.0000408
AC:
1
AN:
24482
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35874
South Asian (SAS)
AF:
0.0000249
AC:
2
AN:
80452
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
47094
Middle Eastern (MID)
AF:
0.000415
AC:
2
AN:
4822
European-Non Finnish (NFE)
AF:
0.0000630
AC:
68
AN:
1079882
Other (OTH)
AF:
0.000279
AC:
16
AN:
57404
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.249
Heterozygous variant carriers
0
40
80
121
161
201
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
20
40
60
80
100
<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
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00232
AC:
347
AN:
149584
Hom.:
0
Cov.:
33
AF XY:
0.00232
AC XY:
170
AN XY:
73124
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00810
AC:
318
AN:
39268
American (AMR)
AF:
0.00105
AC:
16
AN:
15188
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3440
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5148
South Asian (SAS)
AF:
0.000415
AC:
2
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10602
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
286
European-Non Finnish (NFE)
AF:
0.000118
AC:
8
AN:
67854
Other (OTH)
AF:
0.00145
AC:
3
AN:
2068
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.253
Heterozygous variant carriers
0
47
94
141
188
235
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
4
8
12
16
20
<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:
0.00269
Hom.:
0
ExAC
AF:
0.0000178
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 13, 2021
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.413C>T (p.P138L) 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 413, causing the proline (P) at amino acid position 138 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
0.090
BayesDel_addAF
Benign
-0.0030
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.69
D;D
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.19
FATHMM_MKL
Benign
0.64
D
LIST_S2
Benign
0.76
.;T
M_CAP
Pathogenic
0.41
D
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-0.41
T
MutationAssessor
Benign
0.81
L;L
PhyloP100
0.25
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-1.9
N;N
REVEL
Benign
0.27
Sift
Uncertain
0.0090
D;D
Sift4G
Uncertain
0.020
D;D
Polyphen
0.0050
B;B
Vest4
0.075
MutPred
0.38
Loss of glycosylation at P138 (P = 0.0238);Loss of glycosylation at P138 (P = 0.0238);
MVP
0.89
ClinPred
0.023
T
GERP RS
3.9
Varity_R
0.14
gMVP
0.34
Mutation Taster
=88/12
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: rs767626656; hg19: chr6-108882824; API