rs4946935

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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/exons	MANE	Protein	UniProt
FOXO3	NM_001455.4	c.*35-288A>G		intron_variant		ENST00000406360.2	NP_001446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXO3	ENST00000406360.2	c.*35-288A>G		intron_variant		1	NM_001455.4	ENSP00000385824	P1
FOXO3	ENST00000343882.10	c.*35-288A>G		intron_variant		1		ENSP00000339527	P1
FOXO3	ENST00000540898.1	c.*35-288A>G		intron_variant		1		ENSP00000446316

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

Gnomad4 AFR AF: 0.183

Gnomad4 AMR AF: 0.642

Gnomad4 ASJ AF: 0.751

Gnomad4 EAS AF: 0.709

Gnomad4 SAS AF: 0.540

Gnomad4 FIN AF: 0.622

Gnomad4 NFE AF: 0.706

Gnomad4 OTH AF: 0.574

Alfa AF: 0.628 Hom.: 11251

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2019

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs4946935; hg19: chr6-109000742;