Genetic Variant FOXO4:p.Gly83Glu (chrX-71096776-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005938.4(FOXO4):c.248G>A(p.Gly83Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,197,552 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000010 ( 0 hom. 1 hem. )

Consequence

FOXO4
NM_005938.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.31

Publications

0 publications found

Variant links:

Genes affected

FOXO4 (HGNC:7139): (forkhead box O4) This gene encodes a member of the O class of winged helix/forkhead transcription factor family. Proteins encoded by this class are regulated by factors involved in growth and differentiation indicating they play a role in these processes. A translocation involving this gene on chromosome X and the homolog of the Drosophila trithorax gene, encoding a DNA binding protein, located on chromosome 11 is associated with leukemia. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

FOXO4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016977668).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO4	NM_005938.4 link	c.248G>A	p.Gly83Glu	missense_variant	Exon 1 of 3	ENST00000374259.8	NP_005929.2	P98177-1
FOXO4	NM_001170931.2 link	c.171+77G>A		intron_variant	Intron 1 of 3		NP_001164402.1	P98177-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXO4	ENST00000374259.8 link	c.248G>A	p.Gly83Glu	missense_variant	Exon 1 of 3	1	NM_005938.4	ENSP00000363377.3	P98177-1
FOXO4	ENST00000341558.4 link	c.171+77G>A		intron_variant	Intron 1 of 3	5		ENSP00000342209.3	P98177-2
FOXO4	ENST00000466874.1 link	n.447+77G>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000446

AC:

AN:

112149

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00142

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

GnomAD2 exomes

AF:

0.0000929

AC:

AN:

150671

AF XY:

0.000107

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00122

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000101

AC:

AN:

1085351

Hom.:

Cov.:

AF XY:

0.00000282

AC XY:

AN XY:

354013

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26061

American (AMR)

AF:

0.00

AC:

AN:

33601

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19090

East Asian (EAS)

AF:

0.000339

AC:

AN:

29501

South Asian (SAS)

AF:

0.00

AC:

AN:

52533

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39587

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4095

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

835379

Other (OTH)

AF:

0.0000220

AC:

AN:

45504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000357

AC:

AN:

112201

Hom.:

Cov.:

AF XY:

0.0000581

AC XY:

AN XY:

34395

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31007

American (AMR)

AF:

0.00

AC:

AN:

10719

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00114

AC:

AN:

3509

South Asian (SAS)

AF:

0.00

AC:

AN:

2715

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6125

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53039

Other (OTH)

AF:

0.00

AC:

AN:

1540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000919

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.248G>A (p.G83E) alteration is located in exon 1 (coding exon 1) of the FOXO4 gene. This alteration results from a G to A substitution at nucleotide position 248, causing the glycine (G) at amino acid position 83 to be replaced by a glutamic acid (E). 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

0.24

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.57

DEOGEN2

Uncertain

0.58

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.62

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.56

MutationAssessor

Benign

-0.69

PhyloP100

1.3

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.5

REVEL

Benign

0.19

Sift

Benign

1.0

Sift4G

Benign

0.21

Polyphen

0.0

Vest4

0.076

MutPred

0.37

Loss of MoRF binding (P = 0.1006);

MVP

0.57

MPC

0.45

ClinPred

0.038

GERP RS

1.8

PromoterAI

-0.0030

Neutral

(source)

Varity_R

0.19

gMVP

0.74

Mutation Taster

=96/4

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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X-71096776-G-A

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