Genetic Variant FOXO3:p.Pro138Leu (chr6-108561621-C-T) – ACMG Classification: Likely_benign (-2 pts)

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

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]

FOXO3 links:

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
FOXO3	NM_001455.4 link	c.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
FOXO3	ENST00000406360.2 link	c.413C>T	p.Pro138Leu	missense_variant	Exon 1 of 3	1	NM_001455.4	ENSP00000385824.1		O43524-1
FOXO3	ENST00000343882.10 link	c.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.:

Cov.:

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:

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.:

Cov.:

AF XY:

0.000139

AC XY:

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:

AN:

35904

Ashkenazi Jewish (ASJ)

AF:

0.0000408

AC:

AN:

24482

East Asian (EAS)

AF:

0.00

AC:

AN:

35874

South Asian (SAS)

AF:

0.0000249

AC:

AN:

80452

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47094

Middle Eastern (MID)

AF:

0.000415

AC:

AN:

4822

European-Non Finnish (NFE)

AF:

0.0000630

AC:

AN:

1079882

Other (OTH)

AF:

0.000279

AC:

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

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00232

AC:

347

AN:

149584

Hom.:

Cov.:

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:

AN:

15188

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3440

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67854

Other (OTH)

AF:

0.00145

AC:

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

141

188

235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00269

Hom.:

ExAC

AF:

0.0000178

AC:

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

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

D;D

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.76

.;T

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

0.81

L;L

PhyloP100

0.25

PrimateAI

Uncertain

0.74

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

GERP RS

3.9

Varity_R

0.14

gMVP

0.34

Mutation Taster

=88/12

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

6-108561621-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over