Genetic Variant FOXO4:p.Ala87Ser (chrX-71096787-G-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_005938.4(FOXO4):c.259G>T(p.Ala87Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000317 in 1,199,023 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000032 ( 0 hom. 11 hem. )

Consequence

FOXO4
NM_005938.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.44

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26779562).

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.259G>T	p.Ala87Ser	missense_variant	Exon 1 of 3	ENST00000374259.8	NP_005929.2	P98177-1
FOXO4	NM_001170931.2 link	c.172-78G>T		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.259G>T	p.Ala87Ser	missense_variant	Exon 1 of 3	1	NM_005938.4	ENSP00000363377.3	P98177-1
FOXO4	ENST00000341558.4 link	c.172-78G>T		intron_variant	Intron 1 of 3	5		ENSP00000342209.3	P98177-2
FOXO4	ENST00000466874.1 link	n.448-74G>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000934

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000130

AC:

AN:

153531

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000997

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:

0.0000152

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1086843

Hom.:

Cov.:

AF XY:

0.0000310

AC XY:

AN XY:

355007

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26135

American (AMR)

AF:

0.00

AC:

AN:

33753

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19129

East Asian (EAS)

AF:

0.00

AC:

AN:

29570

South Asian (SAS)

AF:

0.00

AC:

AN:

52646

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4111

European-Non Finnish (NFE)

AF:

0.0000419

AC:

AN:

836244

Other (OTH)

AF:

0.00

AC:

AN:

45569

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112180

Hom.:

Cov.:

AF XY:

0.0000582

AC XY:

AN XY:

34346

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30892

American (AMR)

AF:

0.0000934

AC:

AN:

10702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3523

South Asian (SAS)

AF:

0.00

AC:

AN:

2736

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6140

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53098

Other (OTH)

AF:

0.00

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000323

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000833

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.259G>T (p.A87S) alteration is located in exon 1 (coding exon 1) of the FOXO4 gene. This alteration results from a G to T substitution at nucleotide position 259, causing the alanine (A) at amino acid position 87 to be replaced by a serine (S). 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

0.10

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.45

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.63

M_CAP

Pathogenic

0.86

MetaRNN

Benign

0.27

MetaSVM

Uncertain

0.016

MutationAssessor

Benign

0.69

PhyloP100

3.4

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.1

REVEL

Benign

0.27

Sift

Benign

0.15

Sift4G

Benign

0.13

Polyphen

0.15

Vest4

0.13

MVP

0.90

MPC

0.35

ClinPred

0.11

GERP RS

4.0

PromoterAI

-0.0090

Neutral

(source)

Varity_R

0.23

gMVP

0.50

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-71096787-G-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