Genetic Variant NM_001455.4:c.200A>G (chr6-108561408-A-G) – 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_001455.4(FOXO3):c.200A>G(p.Glu67Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,395,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

FOXO3
NM_001455.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.736

Publications

0 publications found

Variant links:

Genes affected

FOXO3 (HGNC:3821): (forkhead box O3) This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. This gene likely functions as a trigger for apoptosis through expression of genes necessary for cell death. Translocation of this gene with the MLL gene is associated with secondary acute leukemia. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]

FOXO3 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=0.21840602).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001455.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXO3	NM_001455.4	MANE Select	c.200A>G	p.Glu67Gly	missense	Exon 1 of 3	NP_001446.1	O43524-1
FOXO3	NM_201559.3		c.200A>G	p.Glu67Gly	missense	Exon 2 of 4	NP_963853.1	O43524-1
FOXO3	NM_001415150.1		c.200A>G	p.Glu67Gly	missense	Exon 2 of 3	NP_001402079.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXO3	ENST00000406360.2	TSL:1 MANE Select	c.200A>G	p.Glu67Gly	missense	Exon 1 of 3	ENSP00000385824.1	O43524-1
FOXO3	ENST00000343882.10	TSL:1	c.200A>G	p.Glu67Gly	missense	Exon 2 of 4	ENSP00000339527.6	O43524-1
FOXO3	ENST00000898147.1		c.200A>G	p.Glu67Gly	missense	Exon 2 of 4	ENSP00000568206.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.17e-7

AC:

AN:

1395162

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

688722

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31470

American (AMR)

AF:

0.00

AC:

AN:

35622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24898

East Asian (EAS)

AF:

0.00

AC:

AN:

35662

South Asian (SAS)

AF:

0.00

AC:

AN:

78562

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4094

European-Non Finnish (NFE)

AF:

9.26e-7

AC:

AN:

1080422

Other (OTH)

AF:

0.00

AC:

AN:

57812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.29

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.90

PhyloP100

0.74

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.30

REVEL

Benign

0.16

Sift

Benign

0.35

Sift4G

Benign

0.29

Polyphen

0.0

Vest4

0.25

MutPred

0.35

Loss of solvent accessibility (P = 0.0013)

MVP

0.96

ClinPred

0.079

GERP RS

2.1

PromoterAI

-0.041

Neutral

(source)

Varity_R

0.066

gMVP

0.18

Mutation Taster

=88/12

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over