Genetic Variant FOXO3:p.Pro5Leu (chr6-108561222-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001455.4(FOXO3):c.14C>T(p.Pro5Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 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: 3.70

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:

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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=0.29481775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO3	NM_001455.4 link	c.14C>T	p.Pro5Leu	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.14C>T	p.Pro5Leu	missense_variant	Exon 1 of 3	1	NM_001455.4	ENSP00000385824.1		O43524-1
FOXO3	ENST00000343882.10 link	c.14C>T	p.Pro5Leu	missense_variant	Exon 2 of 4	1		ENSP00000339527.6		O43524-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000143

AC:

AN:

140154

AF XY:

0.0000260

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000204

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000144

AC:

AN:

1393446

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

688136

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30394

American (AMR)

AF:

0.00

AC:

AN:

35876

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24780

East Asian (EAS)

AF:

0.0000573

AC:

AN:

34896

South Asian (SAS)

AF:

0.00

AC:

AN:

78960

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47422

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4036

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079356

Other (OTH)

AF:

0.00

AC:

AN:

57726

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.038550), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 08, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.14C>T (p.P5L) 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 14, causing the proline (P) at amino acid position 5 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

0.14

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

D;D

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.75

.;T

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.29

T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.4

L;L

PhyloP100

3.7

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.27

Sift

Uncertain

0.011

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.11

B;B

Vest4

0.27

MutPred

0.20

Loss of glycosylation at P5 (P = 0.0163);Loss of glycosylation at P5 (P = 0.0163);

MVP

0.90

ClinPred

0.32

GERP RS

3.8

PromoterAI

0.046

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.33

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

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6-108561222-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over