Genetic Variant FOXO4:p.Lys215Arg (chrX-71100874-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005938.4(FOXO4):c.644A>G(p.Lys215Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000736 in 1,209,169 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., 12 hem., cov: 22)

Exomes 𝑓: 0.000036 ( 0 hom. 8 hem. )

Consequence

FOXO4
NM_005938.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.07

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 made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04333657).

BS2

High Hemizygotes in GnomAd4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO4	NM_005938.4 link	c.644A>G	p.Lys215Arg	missense_variant	Exon 2 of 3	ENST00000374259.8	NP_005929.2	P98177-1
FOXO4	NM_001170931.2 link	c.479A>G	p.Lys160Arg	missense_variant	Exon 3 of 4		NP_001164402.1	P98177-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXO4	ENST00000374259.8 link	c.644A>G	p.Lys215Arg	missense_variant	Exon 2 of 3	1	NM_005938.4	ENSP00000363377.3	P98177-1
FOXO4	ENST00000341558.3 link	c.479A>G	p.Lys160Arg	missense_variant	Exon 3 of 4	5		ENSP00000342209.3	P98177-2
FOXO4	ENST00000464598.1 link	n.*31A>G		downstream_gene_variant		2
FOXO4	ENST00000466874.1 link	n.*102A>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000438

AC:

AN:

111824

Hom.:

Cov.:

AF XY:

0.000353

AC XY:

AN XY:

34010

show subpopulations

Gnomad AFR

AF:

0.00153

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000562

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

GnomAD3 exomes

AF:

0.0000904

AC:

AN:

176966

Hom.:

AF XY:

0.0000623

AC XY:

AN XY:

64254

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000743

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000365

AC:

AN:

1097293

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

362699

show subpopulations

Gnomad4 AFR exome

AF:

0.000720

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000663

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.000391

GnomAD4 genome

AF:

0.000438

AC:

AN:

111876

Hom.:

Cov.:

AF XY:

0.000352

AC XY:

AN XY:

34072

show subpopulations

Gnomad4 AFR

AF:

0.00153

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000564

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000507

Hom.:

Bravo

AF:

0.000385

ExAC

AF:

0.000182

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.644A>G (p.K215R) alteration is located in exon 2 (coding exon 2) of the FOXO4 gene. This alteration results from a A to G substitution at nucleotide position 644, causing the lysine (K) at amino acid position 215 to be replaced by an arginine (R). 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

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;.

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.79

T;T

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.043

T;T

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

3.0

M;.

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.4

N;D

REVEL

Uncertain

0.56

Sift

Benign

0.051

T;T

Sift4G

Uncertain

0.017

D;D

Polyphen

0.24

B;D

Vest4

0.22

MVP

0.96

MPC

0.88

ClinPred

0.22

GERP RS

5.3

Varity_R

0.35

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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