rs4946933

Variant names:

• chr6-108659914-A-G
• rs4946933
• NM_001455.4:c.622-3541A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-108659914-A-G
• chr6-108659914-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001455.4(FOXO3):​c.622-3541A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.931 in 152,268 control chromosomes in the GnomAD database, including 66,098 homozygotes. 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 0.93 (66098 hom., cov: 33)
• Consequence: FOXO3 NM_001455.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.925
• Publications: 6 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.962 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001455.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXO3	NM_001455.4	MANE Select	c.622-3541A>G		intron	N/A	NP_001446.1	O43524-1
	FOXO3	NM_201559.3		c.622-3541A>G		intron	N/A	NP_963853.1	O43524-1
	FOXO3	NM_001415139.1		c.121-3541A>G		intron	N/A	NP_001402068.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXO3	ENST00000406360.2	TSL:1 MANE Select	c.622-3541A>G		intron	N/A	ENSP00000385824.1	O43524-1
	FOXO3	ENST00000343882.10	TSL:1	c.622-3541A>G		intron	N/A	ENSP00000339527.6	O43524-1
	FOXO3	ENST00000540898.1	TSL:1	c.-40+3376A>G		intron	N/A	ENSP00000446316.1	O43524-2

Frequencies

GnomAD3 genomes AF: 0.931 AC: 141588 AN: 152150 Hom.: 66054 Cov.: 33

Gnomad AFR AF: 0.885

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.959

Gnomad ASJ AF: 0.957

Gnomad EAS AF: 0.935

Gnomad SAS AF: 0.778

Gnomad FIN AF: 0.881

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.968

Gnomad OTH AF: 0.938

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.931 AC: 141687 AN: 152268 Hom.: 66098 Cov.: 33 AF XY: 0.925 AC XY: 68854 AN XY: 74450

African (AFR) AF: 0.885 AC: 36765 AN: 41544

American (AMR) AF: 0.959 AC: 14675 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.957 AC: 3322 AN: 3472

East Asian (EAS) AF: 0.935 AC: 4846 AN: 5184

South Asian (SAS) AF: 0.779 AC: 3759 AN: 4824

European-Finnish (FIN) AF: 0.881 AC: 9322 AN: 10584

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.968 AC: 65839 AN: 68032

Other (OTH) AF: 0.939 AC: 1986 AN: 2116

Alfa AF: 0.959 Hom.: 91881

Bravo AF: 0.938

Asia WGS AF: 0.848 AC: 2950 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.070
DANN	Benign	0.49
PhyloP100		-0.93
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4946933; hg19: chr6-108981117;