Genetic Variant FOXO3:c.*1047C>T (chr6-108680839-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000406360.2(FOXO3):c.*1047C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 151,358 control chromosomes in the GnomAD database, including 26,034 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 0.54 ( 26011 hom., cov: 31)

Exomes 𝑓: 0.56 ( 23 hom. )

Consequence

FOXO3
ENST00000406360.2 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.605

Publications

26 publications found

Variant links:

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]

FOXO3 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000406360.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FOXO3	NM_001455.4	MANE Select	c.*1047C>T	3_prime_UTR	Exon 3 of 3	NP_001446.1
FOXO3	NM_201559.3		c.*1047C>T	3_prime_UTR	Exon 4 of 4	NP_963853.1
FOXO3	NM_001415139.1		c.*1047C>T	3_prime_UTR	Exon 3 of 3	NP_001402068.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FOXO3	ENST00000406360.2	TSL:1 MANE Select	c.*1047C>T	3_prime_UTR	Exon 3 of 3	ENSP00000385824.1
FOXO3	ENST00000343882.10	TSL:1	c.*1047C>T	3_prime_UTR	Exon 4 of 4	ENSP00000339527.6
FOXO3	ENST00000540898.1	TSL:1	c.*1047C>T	downstream_gene	N/A	ENSP00000446316.1

Frequencies

GnomAD3 genomes

AF:

0.539

AC:

81417

AN:

151094

Hom.:

26013

Cov.:

show subpopulations

Gnomad AFR

AF:

0.170

Gnomad AMI

AF:

0.813

Gnomad AMR

AF:

0.637

Gnomad ASJ

AF:

0.747

Gnomad EAS

AF:

0.710

Gnomad SAS

AF:

0.522

Gnomad FIN

AF:

0.618

Gnomad MID

AF:

0.542

Gnomad NFE

AF:

0.702

Gnomad OTH

AF:

0.565

GnomAD4 exome

AF:

0.556

AC:

AN:

162

Hom.:

Cov.:

AF XY:

0.477

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.558

AC:

AN:

154

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.539

AC:

81430

AN:

151196

Hom.:

26011

Cov.:

AF XY:

0.537

AC XY:

39653

AN XY:

73808

show subpopulations

African (AFR)

AF:

0.170

AC:

7018

AN:

41332

American (AMR)

AF:

0.637

AC:

9684

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.747

AC:

2562

AN:

3432

East Asian (EAS)

AF:

0.710

AC:

3658

AN:

5152

South Asian (SAS)

AF:

0.523

AC:

2508

AN:

4792

European-Finnish (FIN)

AF:

0.618

AC:

6404

AN:

10356

Middle Eastern (MID)

AF:

0.542

AC:

156

AN:

288

European-Non Finnish (NFE)

AF:

0.702

AC:

47523

AN:

67660

Other (OTH)

AF:

0.567

AC:

1182

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1479

2958

4436

5915

7394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

680

1360

2040

2720

3400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.606

Hom.:

10117

Bravo

AF:

0.529

Asia WGS

AF:

0.553

AC:

1925

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

8.7

(source)

DANN

Benign

0.53

PhyloP100

0.60

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over