X-71096725-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005938.4(FOXO4):c.197C>G(p.Pro66Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000747 in 1,204,439 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000073 ( 0 hom. 3 hem. )

Consequence

FOXO4
NM_005938.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.652

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1901724).

BS2

High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO4	NM_005938.4 link	c.197C>G	p.Pro66Arg	missense_variant	Exon 1 of 3	ENST00000374259.8	NP_005929.2	P98177-1
FOXO4	NM_001170931.2 link	c.171+26C>G		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.197C>G	p.Pro66Arg	missense_variant	Exon 1 of 3	1	NM_005938.4	ENSP00000363377.3	P98177-1
FOXO4	ENST00000341558.4 link	c.171+26C>G		intron_variant	Intron 1 of 3	5		ENSP00000342209.3	P98177-2
FOXO4	ENST00000466874.1 link	n.447+26C>G		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.00000891

AC:

AN:

112267

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:

0.000281

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:

0.0000244

AC:

AN:

163927

AF XY:

0.0000186

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000321

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000732

AC:

AN:

1092172

Hom.:

Cov.:

AF XY:

0.00000837

AC XY:

AN XY:

358410

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26259

American (AMR)

AF:

0.00

AC:

AN:

34653

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19255

East Asian (EAS)

AF:

0.000234

AC:

AN:

29854

South Asian (SAS)

AF:

0.00

AC:

AN:

53151

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40005

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4111

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

839069

Other (OTH)

AF:

0.0000218

AC:

AN:

45815

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000891

AC:

AN:

112267

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34407

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30942

American (AMR)

AF:

0.00

AC:

AN:

10701

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.000281

AC:

AN:

3559

South Asian (SAS)

AF:

0.00

AC:

AN:

2718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53106

Other (OTH)

AF:

0.00

AC:

AN:

1519

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.197C>G (p.P66R) alteration is located in exon 1 (coding exon 1) of the FOXO4 gene. This alteration results from a C to G substitution at nucleotide position 197, causing the proline (P) at amino acid position 66 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

0.099

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Uncertain

0.73

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.64

M_CAP

Pathogenic

0.82

MetaRNN

Benign

0.19

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

1.1

PhyloP100

0.65

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.23

Sift

Benign

0.036

Sift4G

Benign

0.076

Polyphen

0.31

Vest4

0.080

MutPred

0.31

Loss of glycosylation at S71 (P = 0.1023);

MVP

0.78

MPC

1.1

ClinPred

0.093

GERP RS

4.3

PromoterAI

0.025

Neutral

(source)

Varity_R

0.42

gMVP

0.63

Mutation Taster

=73/27

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-71096725-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over