Variant chr13-40560023-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_002015.4(FOXO1):c.1468C>T(p.Arg490Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

FOXO1
NM_002015.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.41

Variant links:

Genes affected

FOXO1 (HGNC:3819): (forkhead box O1) This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. The specific function of this gene has not yet been determined; however, it may play a role in myogenic growth and differentiation. Translocation of this gene with PAX3 has been associated with alveolar rhabdomyosarcoma. [provided by RefSeq, Jul 2008]

FOXO1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.818

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FOXO1	NM_002015.4 linkuse as main transcript	c.1468C>T	p.Arg490Trp	missense_variant	2/3	ENST00000379561.6	NP_002006.2
FOXO1	XM_011535008.3 linkuse as main transcript	c.925C>T	p.Arg309Trp	missense_variant	2/3		XP_011533310.1
FOXO1	XM_011535010.3 linkuse as main transcript	c.757C>T	p.Arg253Trp	missense_variant	2/3		XP_011533312.1
FOXO1	XM_047430204.1 linkuse as main transcript	c.757C>T	p.Arg253Trp	missense_variant	2/3		XP_047286160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXO1	ENST00000379561.6 linkuse as main transcript	c.1468C>T	p.Arg490Trp	missense_variant	2/3	1	NM_002015.4	ENSP00000368880	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251286

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135798

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

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

Jan 04, 2022

The c.1468C>T (p.R490W) alteration is located in exon 2 (coding exon 2) of the FOXO1 gene. This alteration results from a C to T substitution at nucleotide position 1468, causing the arginine (R) at amino acid position 490 to be replaced by a tryptophan (W). 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

0.16

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.82

MetaSVM

Pathogenic

0.92

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

0.89

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.55

Sift

Uncertain

0.022

Sift4G

Uncertain

0.032

Polyphen

1.0

Vest4

0.77

MVP

0.90

MPC

0.85

ClinPred

0.53

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.22

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