Genetic Variant FOXO4:p.Glu170Gln (chrX-71100738-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_005938.4(FOXO4):c.508G>C(p.Glu170Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000581 in 1,205,439 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E170K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000055 ( 0 hom. 1 hem. )

Consequence

FOXO4
NM_005938.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.51

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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO4	NM_005938.4 link	c.508G>C	p.Glu170Gln	missense_variant	Exon 2 of 3	ENST00000374259.8	NP_005929.2	P98177-1
FOXO4	NM_001170931.2 link	c.343G>C	p.Glu115Gln	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.508G>C	p.Glu170Gln	missense_variant	Exon 2 of 3	1	NM_005938.4	ENSP00000363377.3	P98177-1
FOXO4	ENST00000341558.4 link	c.343G>C	p.Glu115Gln	missense_variant	Exon 3 of 4	5		ENSP00000342209.3	P98177-2
FOXO4	ENST00000464598.1 link	n.201G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2
FOXO4	ENST00000466874.1 link	n.623G>C		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.00000905

AC:

AN:

110451

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1094988

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

360740

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26307

American (AMR)

AF:

0.00

AC:

AN:

34881

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19251

East Asian (EAS)

AF:

0.00

AC:

AN:

30132

South Asian (SAS)

AF:

0.00

AC:

AN:

53826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40445

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4115

European-Non Finnish (NFE)

AF:

0.00000595

AC:

AN:

840086

Other (OTH)

AF:

0.0000218

AC:

AN:

45945

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000905

AC:

AN:

110451

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32725

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30273

American (AMR)

AF:

0.00

AC:

AN:

10400

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2633

East Asian (EAS)

AF:

0.00

AC:

AN:

3515

South Asian (SAS)

AF:

0.00

AC:

AN:

2525

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5932

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52772

Other (OTH)

AF:

0.00

AC:

AN:

1485

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000151

AC:

ExAC

AF:

0.00000826

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

9.5

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.7

D;D

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.065

T;T

Polyphen

0.74

P;D

Vest4

0.61

MVP

0.97

MPC

0.79

ClinPred

0.88

GERP RS

4.3

Varity_R

0.93

gMVP

0.74

Mutation Taster

=34/66

disease causing

(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-71100738-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over