6-108561627-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001455.4(FOXO3):​c.419C>T​(p.Ala140Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0464 in 1,555,948 control chromosomes in the GnomAD database, including 1,924 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.036 ( 133 hom., cov: 33)
Exomes 𝑓: 0.048 ( 1791 hom. )

Consequence

FOXO3
NM_001455.4 missense

Scores

3
15

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.35

Publications

10 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: Benign. The variant received -14 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0016524792).
BP6
Variant 6-108561627-C-T is Benign according to our data. Variant chr6-108561627-C-T is described in ClinVar as [Benign]. Clinvar id is 770927.Status of the report is criteria_provided_single_submitter, 1 stars.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0509 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FOXO3NM_001455.4 linkc.419C>T p.Ala140Val 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.419C>T p.Ala140Val missense_variant Exon 1 of 3 1 NM_001455.4 ENSP00000385824.1 O43524-1
FOXO3ENST00000343882.10 linkc.419C>T p.Ala140Val missense_variant Exon 2 of 4 1 ENSP00000339527.6 O43524-1

Frequencies

GnomAD3 genomes
AF:
0.0358
AC:
5440
AN:
151996
Hom.:
134
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00869
Gnomad AMI
AF:
0.00768
Gnomad AMR
AF:
0.0362
Gnomad ASJ
AF:
0.0564
Gnomad EAS
AF:
0.00174
Gnomad SAS
AF:
0.0536
Gnomad FIN
AF:
0.0361
Gnomad MID
AF:
0.0994
Gnomad NFE
AF:
0.0524
Gnomad OTH
AF:
0.0417
GnomAD2 exomes
AF:
0.0418
AC:
6200
AN:
148252
AF XY:
0.0453
show subpopulations
Gnomad AFR exome
AF:
0.00585
Gnomad AMR exome
AF:
0.0258
Gnomad ASJ exome
AF:
0.0583
Gnomad EAS exome
AF:
0.000286
Gnomad FIN exome
AF:
0.0370
Gnomad NFE exome
AF:
0.0516
Gnomad OTH exome
AF:
0.0479
GnomAD4 exome
AF:
0.0475
AC:
66700
AN:
1403834
Hom.:
1791
Cov.:
33
AF XY:
0.0480
AC XY:
33299
AN XY:
694326
show subpopulations
African (AFR)
AF:
0.00768
AC:
242
AN:
31514
American (AMR)
AF:
0.0281
AC:
1034
AN:
36788
Ashkenazi Jewish (ASJ)
AF:
0.0566
AC:
1400
AN:
24736
East Asian (EAS)
AF:
0.000166
AC:
6
AN:
36078
South Asian (SAS)
AF:
0.0620
AC:
5028
AN:
81080
European-Finnish (FIN)
AF:
0.0364
AC:
1732
AN:
47584
Middle Eastern (MID)
AF:
0.0921
AC:
454
AN:
4928
European-Non Finnish (NFE)
AF:
0.0501
AC:
54248
AN:
1083066
Other (OTH)
AF:
0.0440
AC:
2556
AN:
58060
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
3829
7659
11488
15318
19147
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
1978
3956
5934
7912
9890
<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:
0.0357
AC:
5438
AN:
152114
Hom.:
133
Cov.:
33
AF XY:
0.0348
AC XY:
2587
AN XY:
74356
show subpopulations
African (AFR)
AF:
0.00871
AC:
362
AN:
41564
American (AMR)
AF:
0.0361
AC:
553
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.0564
AC:
195
AN:
3458
East Asian (EAS)
AF:
0.00174
AC:
9
AN:
5158
South Asian (SAS)
AF:
0.0535
AC:
258
AN:
4826
European-Finnish (FIN)
AF:
0.0361
AC:
383
AN:
10598
Middle Eastern (MID)
AF:
0.0966
AC:
28
AN:
290
European-Non Finnish (NFE)
AF:
0.0524
AC:
3556
AN:
67902
Other (OTH)
AF:
0.0413
AC:
87
AN:
2108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.489
Heterozygous variant carriers
0
270
539
809
1078
1348
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
70
140
210
280
350
<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:
0.0332
Hom.:
30
Bravo
AF:
0.0336
ESP6500AA
AF:
0.00734
AC:
25
ESP6500EA
AF:
0.0457
AC:
331
ExAC
AF:
0.0310
AC:
3525

ClinVar

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

Submissions by phenotype

not provided Benign:1
Dec 31, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.078
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.44
T;T
Eigen
Benign
-0.41
Eigen_PC
Benign
-0.30
FATHMM_MKL
Benign
0.55
D
LIST_S2
Benign
0.25
.;T
MetaRNN
Benign
0.0017
T;T
MetaSVM
Benign
-0.47
T
MutationAssessor
Benign
0.26
N;N
PhyloP100
1.4
PrimateAI
Uncertain
0.66
T
PROVEAN
Benign
-1.3
N;N
REVEL
Benign
0.19
Sift
Benign
0.17
T;T
Sift4G
Benign
0.11
T;T
Polyphen
0.0010
B;B
Vest4
0.020
ClinPred
0.0089
T
GERP RS
3.0
Varity_R
0.086
gMVP
0.53
Mutation Taster
=88/12
polymorphism (auto)

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: rs111556510; hg19: chr6-108882830; COSMIC: COSV59628700; API