Genetic Variant FOXO4:p.Gly83Ala (chrX-71096776-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005938.4(FOXO4):c.248G>C(p.Gly83Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000921 in 1,085,352 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. G83E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

FOXO4
NM_005938.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.31

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16377914).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO4	NM_005938.4 link	c.248G>C	p.Gly83Ala	missense_variant	Exon 1 of 3	ENST00000374259.8	NP_005929.2	P98177-1
FOXO4	NM_001170931.2 link	c.171+77G>C		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.248G>C	p.Gly83Ala	missense_variant	Exon 1 of 3	1	NM_005938.4	ENSP00000363377.3	P98177-1
FOXO4	ENST00000341558.4 link	c.171+77G>C		intron_variant	Intron 1 of 3	5		ENSP00000342209.3	P98177-2
FOXO4	ENST00000466874.1 link	n.447+77G>C		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.21e-7

AC:

AN:

1085352

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

354014

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26061

American (AMR)

AF:

0.00

AC:

AN:

33601

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19090

East Asian (EAS)

AF:

0.00

AC:

AN:

29501

South Asian (SAS)

AF:

0.00

AC:

AN:

52533

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39587

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4095

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

835380

Other (OTH)

AF:

0.00

AC:

AN:

45504

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.36

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.73

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.0

PhyloP100

1.3

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.18

REVEL

Benign

0.20

Sift

Benign

0.82

Sift4G

Benign

0.60

Polyphen

0.0010

Vest4

0.092

MutPred

0.34

Loss of loop (P = 0.1258);

MVP

0.73

MPC

0.37

ClinPred

0.063

GERP RS

1.8

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.069

gMVP

0.69

Mutation Taster

=97/3

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over