6-108663614-A-G

Position:

• chr6-108663614-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001455.4(FOXO3):​c.781A>G​(p.Thr261Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T261I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FOXO3 NM_001455.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32142067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXO3	NM_001455.4	c.781A>G	p.Thr261Ala	missense_variant	2/3	ENST00000406360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXO3	ENST00000406360.2	c.781A>G	p.Thr261Ala	missense_variant	2/3	1	NM_001455.4	P1
FOXO3	ENST00000343882.10	c.781A>G	p.Thr261Ala	missense_variant	3/4	1		P1
FOXO3	ENST00000540898.1	c.121A>G	p.Thr41Ala	missense_variant	2/3	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2024

The c.781A>G (p.T261A) alteration is located in exon 2 (coding exon 2) of the FOXO3 gene. This alteration results from a A to G substitution at nucleotide position 781, causing the threonine (T) at amino acid position 261 to be replaced by an alanine (A). 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	0.070
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Benign	0.40
DEOGEN2	Benign	0.33	T;T;.
Eigen	Benign	0.073
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	-0.11	N;N;.
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.14	N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.72	T;T;T
Sift4G	Benign	0.86	T;T;T
Polyphen		0.75	P;P;.
Vest4		0.43
MutPred		0.23		Loss of phosphorylation at T261 (P = 0.0063);Loss of phosphorylation at T261 (P = 0.0063);.;
MVP		0.88
ClinPred		0.82	D
GERP RS		5.7
Varity_R		0.15
gMVP		0.40

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-108984817;