6-108561581-G-A

Variant names:

• chr6-108561581-G-A
• rs1295839778
• NM_001455.4:c.373G>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001455.4(FOXO3):​c.373G>A​(p.Ala125Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000262 in 1,489,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A125V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: FOXO3 NM_001455.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.853

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04350406).
• BP6: Variant 6-108561581-G-A is Benign according to our data. Variant chr6-108561581-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3851440.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO3	NM_001455.4	c.373G>A	p.Ala125Thr	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.373G>A	p.Ala125Thr	missense_variant	Exon 1 of 3	1	NM_001455.4	ENSP00000385824.1
FOXO3	ENST00000343882.10	c.373G>A	p.Ala125Thr	missense_variant	Exon 2 of 4	1		ENSP00000339527.6

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152066 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000899 AC: 7 AN: 77878 Hom.: 0 AF XY: 0.0000728 AC XY: 3 AN XY: 41208

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000307

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.000422

GnomAD4 exome AF: 0.0000224 AC: 30 AN: 1337084 Hom.: 0 Cov.: 32 AF XY: 0.0000183 AC XY: 12 AN XY: 655334

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000305

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000142

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000152

Gnomad4 OTH exome AF: 0.0000721

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152066 Hom.: 0 Cov.: 33 AF XY: 0.0000808 AC XY: 6 AN XY: 74246

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 15, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Benign	0.83
DEOGEN2	Benign	0.33	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.54	.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.12	N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.20	N;N
REVEL	Benign	0.23
Sift	Benign	0.85	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.0	B;B
Vest4		0.014
MutPred		0.23		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MVP		0.59
ClinPred		0.038	T
GERP RS		0.28
Varity_R		0.028
gMVP		0.29

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: rs1295839778; hg19: chr6-108882784;