6-108561222-C-T

Variant summary

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

The NM_001455.4(FOXO3):c.14C>T(p.Pro5Leu) variant causes a missense change. 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXO3 NM_001455.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.70

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=0.29481775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXO3	NM_001455.4	c.14C>T	p.Pro5Leu	missense_variant	1/3	ENST00000406360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXO3	ENST00000406360.2	c.14C>T	p.Pro5Leu	missense_variant	1/3	1	NM_001455.4	P1
FOXO3	ENST00000343882.10	c.14C>T	p.Pro5Leu	missense_variant	2/4	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000144 AC: 2 AN: 1393446 Hom.: 0 Cov.: 32 AF XY: 0.00000291 AC XY: 2 AN XY: 688136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000573

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Aug 08, 2023

The c.14C>T (p.P5L) alteration is located in exon 1 (coding exon 1) of the FOXO3 gene. This alteration results from a C to T substitution at nucleotide position 14, causing the proline (P) at amino acid position 5 to be replaced by a leucine (L). 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	0.14
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;D
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.34	N
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.80	N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.27
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.11	B;B
Vest4		0.27
MutPred		0.20		Loss of glycosylation at P5 (P = 0.0163);Loss of glycosylation at P5 (P = 0.0163);
MVP		0.90
ClinPred		0.32	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.33

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

Other links and lift over

dbSNP: rs1463974336; hg19: chr6-108882425;