Variant chrX-71100900-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005938.4(FOXO4):c.670G>A(p.Glu224Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000661 in 1,209,746 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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 0.0000089 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000064 ( 0 hom. 1 hem. )

Consequence

FOXO4
NM_005938.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.21

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19767633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXO4	NM_005938.4 linkuse as main transcript	c.670G>A	p.Glu224Lys	missense_variant	2/3	ENST00000374259.8	NP_005929.2	P98177-1
FOXO4	NM_001170931.2 linkuse as main transcript	c.505G>A	p.Glu169Lys	missense_variant	3/4		NP_001164402.1	P98177-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXO4	ENST00000374259.8 linkuse as main transcript	c.670G>A	p.Glu224Lys	missense_variant	2/3	1	NM_005938.4	ENSP00000363377.3		P98177-1
FOXO4	ENST00000341558.3 linkuse as main transcript	c.505G>A	p.Glu169Lys	missense_variant	3/4	5		ENSP00000342209.3		P98177-2

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112100

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34282

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000939

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

GnomAD3 exomes

AF:

0.0000113

AC:

AN:

177288

Hom.:

AF XY:

0.00

AC XY:

AN XY:

64350

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000736

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000638

AC:

AN:

1097646

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363030

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000569

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:

0.00000594

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000892

AC:

AN:

112100

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000939

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

ExAC

AF:

0.00000827

AC:

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

May 24, 2023

The c.670G>A (p.E224K) alteration is located in exon 2 (coding exon 2) of the FOXO4 gene. This alteration results from a G to A substitution at nucleotide position 670, causing the glutamic acid (E) at amino acid position 224 to be replaced by a lysine (K). 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

-0.030

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.71

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.20

T;T

MetaSVM

Uncertain

0.46

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.1

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.14

T;T

Sift4G

Benign

0.45

T;T

Polyphen

0.97

D;B

Vest4

0.13

MutPred

0.35

Gain of methylation at E224 (P = 0.0106);.;

MVP

0.93

MPC

0.42

ClinPred

0.24

GERP RS

4.3

Varity_R

0.093

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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