6-108663580-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001455.4(FOXO3):c.747G>A(p.Arg249=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00669 in 1,613,668 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0056 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0068 (38 hom.)
• Consequence: FOXO3 NM_001455.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.119

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 6-108663580-G-A is Benign according to our data. Variant chr6-108663580-G-A is described in ClinVar as [Benign]. Clinvar id is 769687.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.119 with no splicing effect.
• BS2: High AC in GnomAd at 853 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXO3	NM_001455.4	c.747G>A	p.Arg249=	synonymous_variant	2/3	ENST00000406360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXO3	ENST00000406360.2	c.747G>A	p.Arg249=	synonymous_variant	2/3	1	NM_001455.4	P1
FOXO3	ENST00000343882.10	c.747G>A	p.Arg249=	synonymous_variant	3/4	1		P1
FOXO3	ENST00000540898.1	c.87G>A	p.Arg29=	synonymous_variant	2/3	1

Frequencies

GnomAD3 genomes AF: 0.00561 AC: 853 AN: 152168 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00781

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00901

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00581 AC: 1437 AN: 247332 Hom.: 8 AF XY: 0.00588 AC XY: 791 AN XY: 134536

Gnomad AFR exome AF: 0.00132

Gnomad AMR exome AF: 0.00221

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.00695

Gnomad NFE exome AF: 0.00886

Gnomad OTH exome AF: 0.00666

GnomAD4 exome AF: 0.00680 AC: 9940 AN: 1461382 Hom.: 38 Cov.: 32 AF XY: 0.00672 AC XY: 4888 AN XY: 726992

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00203

Gnomad4 FIN exome AF: 0.00644

Gnomad4 NFE exome AF: 0.00776

Gnomad4 OTH exome AF: 0.00558

GnomAD4 genome AF: 0.00560 AC: 853 AN: 152286 Hom.: 3 Cov.: 31 AF XY: 0.00526 AC XY: 392 AN XY: 74456

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00951

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00781

Gnomad4 NFE AF: 0.00901

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00841 Hom.: 2

Bravo AF: 0.00467

EpiCase AF: 0.00763

EpiControl AF: 0.00795

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

Invitae

May 30, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	8.2
Dann	Benign	0.59

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: rs61756661; hg19: chr6-108984783; COSMIC: COSV59627579;