Variant X-71100792-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005938.4(FOXO4):c.562G>A(p.Gly188Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,097,354 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000015 ( 0 hom. 9 hem. )

Failed GnomAD Quality Control

Consequence

FOXO4
NM_005938.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.69

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:

FOXO4 (HGNC:):

FOXO4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXO4	NM_005938.4 linkuse as main transcript	c.562G>A	p.Gly188Ser	missense_variant	2/3	ENST00000374259.8	NP_005929.2	P98177-1
FOXO4	NM_001170931.2 linkuse as main transcript	c.397G>A	p.Gly133Ser	missense_variant	3/4		NP_001164402.1	P98177-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FOXO4	ENST00000374259.8 linkuse as main transcript	c.562G>A	p.Gly188Ser	missense_variant	2/3	1	NM_005938.4	ENSP00000363377.3	P98177-1
FOXO4	ENST00000341558.3 linkuse as main transcript	c.397G>A	p.Gly133Ser	missense_variant	3/4	5		ENSP00000342209.3	P98177-2
FOXO4	ENST00000464598.1 linkuse as main transcript	n.255G>A		non_coding_transcript_exon_variant	2/2	2
FOXO4	ENST00000466874.1 linkuse as main transcript	n.*20G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111779

Hom.:

Cov.:

AF XY:

0.0000589

AC XY:

AN XY:

33957

show subpopulations

Gnomad AFR

AF:

0.0000325

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000566

AC:

AN:

176768

Hom.:

AF XY:

0.0000155

AC XY:

AN XY:

64340

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000534

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000146

AC:

AN:

1097354

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

362766

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000111

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000713

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000179

AC:

AN:

111779

Hom.:

Cov.:

AF XY:

0.0000589

AC XY:

AN XY:

33957

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000169

Hom.:

Bravo

AF:

0.00000378

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

Sep 03, 2024

The c.562G>A (p.G188S) 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 562, causing the glycine (G) at amino acid position 188 to be replaced by a serine (S). 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

0.17

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;.

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.58

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

2.9

M;.

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.55

MutPred

0.34

Gain of glycosylation at G188 (P = 0.0091);.;

MVP

0.98

MPC

1.1

ClinPred

0.96

GERP RS

5.0

Varity_R

0.96

gMVP

0.76

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

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