NM_001455.4:c.263T>G

Variant names:

• chr6-108561471-T-G
• rs1415832829
• NM_001455.4:c.263T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001455.4(FOXO3):​c.263T>G​(p.Leu88Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000131 in 1,528,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: FOXO3 NM_001455.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33567327).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXO3	NM_001455.4	MANE Select	c.263T>G	p.Leu88Arg	missense	Exon 1 of 3	NP_001446.1	O43524-1
	FOXO3	NM_201559.3		c.263T>G	p.Leu88Arg	missense	Exon 2 of 4	NP_963853.1	O43524-1
	FOXO3	NM_001415150.1		c.263T>G	p.Leu88Arg	missense	Exon 2 of 3	NP_001402079.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXO3	ENST00000406360.2	TSL:1 MANE Select	c.263T>G	p.Leu88Arg	missense	Exon 1 of 3	ENSP00000385824.1	O43524-1
	FOXO3	ENST00000343882.10	TSL:1	c.263T>G	p.Leu88Arg	missense	Exon 2 of 4	ENSP00000339527.6	O43524-1
	FOXO3	ENST00000898147.1		c.263T>G	p.Leu88Arg	missense	Exon 2 of 4	ENSP00000568206.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

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

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1375850 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 678134

African (AFR) AF: 0.00 AC: 0 AN: 30760

American (AMR) AF: 0.00 AC: 0 AN: 34274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23730

East Asian (EAS) AF: 0.0000289 AC: 1 AN: 34614

South Asian (SAS) AF: 0.00 AC: 0 AN: 75650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4012

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1072470

Other (OTH) AF: 0.00 AC: 0 AN: 57114

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74394

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.21
Sift	Benign	0.54	T
Sift4G	Benign	0.19	T
Polyphen		0.0010	B
Vest4		0.29
MutPred		0.36		Gain of methylation at L88 (P = 0.0095)
MVP		0.80
ClinPred		0.073	T
GERP RS		3.3
Varity_R		0.23
gMVP		0.23
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs1415832829; hg19: chr6-108882674;