Variant 6-108561564-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001455.4(FOXO3):c.356T>A(p.Leu119Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,438,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

FOXO3
NM_001455.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.311

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22730032).

BS2

High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXO3	NM_001455.4 linkuse as main transcript	c.356T>A	p.Leu119Gln	missense_variant	1/3	ENST00000406360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXO3	ENST00000406360.2 linkuse as main transcript	c.356T>A	p.Leu119Gln	missense_variant	1/3	1	NM_001455.4	P1	O43524-1
FOXO3	ENST00000343882.10 linkuse as main transcript	c.356T>A	p.Leu119Gln	missense_variant	2/4	1		P1	O43524-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000241

AC:

AN:

1286130

Hom.:

Cov.:

AF XY:

0.0000223

AC XY:

AN XY:

627600

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000299

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152012

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2023

The c.356T>A (p.L119Q) alteration is located in exon 1 (coding exon 1) of the FOXO3 gene. This alteration results from a T to A substitution at nucleotide position 356, causing the leucine (L) at amino acid position 119 to be replaced by a glutamine (Q). 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

0.064

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.34

T;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.60

.;T

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

0.95

N;N

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.49

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.12

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.056

B;B

Vest4

0.16

MutPred

0.17

Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);

MVP

0.75

ClinPred

0.066

GERP RS

1.2

Varity_R

0.062

gMVP

0.38

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over