rs1536057

Variant names:

• chr6-108564420-C-T
• rs1536057
• NM_001455.4:c.621+2591C>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.621+2591C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 152,096 control chromosomes in the GnomAD database, including 7,000 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 0.30 (7000 hom., cov: 33)
• Consequence: FOXO3 NM_001455.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.515
• Publications: 16 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO3	NM_001455.4	c.621+2591C>T		intron_variant	Intron 1 of 2	ENST00000406360.2	NP_001446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXO3	ENST00000406360.2	c.621+2591C>T		intron_variant	Intron 1 of 2	1	NM_001455.4	ENSP00000385824.1
FOXO3	ENST00000343882.10	c.621+2591C>T		intron_variant	Intron 2 of 3	1		ENSP00000339527.6

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45594 AN: 151978 Hom.: 7002 Cov.: 33

Gnomad AFR AF: 0.368

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.310

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

GnomAD4 genome AF: 0.300 AC: 45611 AN: 152096 Hom.: 7000 Cov.: 33 AF XY: 0.296 AC XY: 21975 AN XY: 74354

African (AFR) AF: 0.367 AC: 15218 AN: 41458

American (AMR) AF: 0.293 AC: 4475 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 785 AN: 3470

East Asian (EAS) AF: 0.217 AC: 1127 AN: 5182

South Asian (SAS) AF: 0.208 AC: 1005 AN: 4830

European-Finnish (FIN) AF: 0.265 AC: 2797 AN: 10574

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19233 AN: 67974

Other (OTH) AF: 0.310 AC: 655 AN: 2114

Alfa AF: 0.292 Hom.: 17976

Bravo AF: 0.307

Asia WGS AF: 0.242 AC: 839 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.3
DANN	Benign	0.60
PhyloP100		-0.52
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: rs1536057; hg19: chr6-108885623; COSMIC: COSV59631478;