6-108561621-C-G

Variant names:

• chr6-108561621-C-G
• rs767626656
• NM_001455.4:c.413C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001455.4(FOXO3):​c.413C>G​(p.Pro138Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 151,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: FOXO3 NM_001455.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.249

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1974237).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO3	NM_001455.4	c.413C>G	p.Pro138Arg	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.413C>G	p.Pro138Arg	missense_variant	Exon 1 of 3	1	NM_001455.4	ENSP00000385824.1
FOXO3	ENST00000343882.10	c.413C>G	p.Pro138Arg	missense_variant	Exon 2 of 4	1		ENSP00000339527.6

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151056 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151056 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 73782

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Uncertain	0.69	D;D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.71	.;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.029	D;D
Polyphen		0.0060	B;B
Vest4		0.064
MutPred		0.37		Loss of glycosylation at P138 (P = 0.0238);Loss of glycosylation at P138 (P = 0.0238);
MVP		0.89
ClinPred		0.19	T
GERP RS		3.9
Varity_R		0.20
gMVP		0.39

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: rs767626656; hg19: chr6-108882824;