NM_001455.4:c.419C>A

Variant names:

• chr6-108561627-C-A
• rs111556510
• NM_001455.4:c.419C>A

Variant summary

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

The NM_001455.4(FOXO3):​c.419C>A​(p.Ala140Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 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. A140V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FOXO3 NM_001455.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35
• Publications: 10 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=0.36465228).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO3	NM_001455.4	c.419C>A	p.Ala140Glu	missense_variant	Exon 1 of 3	ENST00000406360.2	NP_001446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXO3	ENST00000406360.2	c.419C>A	p.Ala140Glu	missense_variant	Exon 1 of 3	1	NM_001455.4	ENSP00000385824.1
FOXO3	ENST00000343882.10	c.419C>A	p.Ala140Glu	missense_variant	Exon 2 of 4	1		ENSP00000339527.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.21	.;T
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.1	L;L
PhyloP100		1.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.26
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		0.49	P;P
Vest4		0.21
MutPred		0.29		Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);
MVP		0.79
ClinPred		0.57	D
GERP RS		3.0
Varity_R		0.29
gMVP		0.63
Mutation Taster		=88/12	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: rs111556510; hg19: chr6-108882830;