rs4946935

Variant names:

• chr6-108679539-A-G
• rs4946935
• NM_001455.4:c.*35-288A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-108679539-A-G
• chr6-108679539-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001455.4(FOXO3):​c.*35-288A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 151,954 control chromosomes in the GnomAD database, including 26,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.55 (26594 hom., cov: 31)
• Consequence: FOXO3 NM_001455.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0340
• Publications: 40 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-108679539-A-G is Benign according to our data. Variant chr6-108679539-A-G is described in ClinVar as Benign. ClinVar VariationId is 1277545.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO3	NM_001455.4	c.*35-288A>G		intron_variant	Intron 2 of 2	ENST00000406360.2	NP_001446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXO3	ENST00000406360.2	c.*35-288A>G		intron_variant	Intron 2 of 2	1	NM_001455.4	ENSP00000385824.1
FOXO3	ENST00000343882.10	c.*35-288A>G		intron_variant	Intron 3 of 3	1		ENSP00000339527.6
FOXO3	ENST00000540898.1	c.*35-288A>G		intron_variant	Intron 2 of 2	1		ENSP00000446316.1

Frequencies

GnomAD3 genomes AF: 0.546 AC: 82850 AN: 151836 Hom.: 26595 Cov.: 31

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.813

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.751

Gnomad EAS AF: 0.710

Gnomad SAS AF: 0.539

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.706

Gnomad OTH AF: 0.572

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

GnomAD4 genome AF: 0.545 AC: 82872 AN: 151954 Hom.: 26594 Cov.: 31 AF XY: 0.545 AC XY: 40447 AN XY: 74270

African (AFR) AF: 0.183 AC: 7563 AN: 41424

American (AMR) AF: 0.642 AC: 9792 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.751 AC: 2609 AN: 3472

East Asian (EAS) AF: 0.709 AC: 3654 AN: 5152

South Asian (SAS) AF: 0.540 AC: 2602 AN: 4816

European-Finnish (FIN) AF: 0.622 AC: 6567 AN: 10566

Middle Eastern (MID) AF: 0.551 AC: 161 AN: 292

European-Non Finnish (NFE) AF: 0.706 AC: 47969 AN: 67942

Other (OTH) AF: 0.574 AC: 1214 AN: 2114

Alfa AF: 0.626 Hom.: 13547

Bravo AF: 0.534

Asia WGS AF: 0.564 AC: 1960 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29234056) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.2
DANN	Benign	0.50
PhyloP100		-0.034
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs4946935; hg19: chr6-109000742;