6-108561282-A-G

Variant names:

• chr6-108561282-A-G
• rs1223937209
• NM_001455.4:c.74A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001455.4(FOXO3):​c.74A>G​(p.Gln25Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 4.41

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO3	NM_001455.4	c.74A>G	p.Gln25Arg	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.74A>G	p.Gln25Arg	missense_variant	Exon 1 of 3	1	NM_001455.4	ENSP00000385824.1
FOXO3	ENST00000343882.10	c.74A>G	p.Gln25Arg	missense_variant	Exon 2 of 4	1		ENSP00000339527.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000142 AC: 2 AN: 1412820 Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1 AN XY: 699084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.74A>G (p.Q25R) alteration is located in exon 1 (coding exon 1) of the FOXO3 gene. This alteration results from a A to G substitution at nucleotide position 74, causing the glutamine (Q) at amino acid position 25 to be replaced by an arginine (R). 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	0.23
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Uncertain	0.60	D;D
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Uncertain	-0.045	T
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.059	T;T
Sift4G	Uncertain	0.027	D;D
Polyphen		0.33	B;B
Vest4		0.27
MutPred		0.18		Gain of glycosylation at P24 (P = 0.0755);Gain of glycosylation at P24 (P = 0.0755);
MVP		0.90
ClinPred		0.51	D
GERP RS		3.1
Varity_R		0.14
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1223937209; hg19: chr6-108882485;