Genetic Variant FOXO1:c.*1254G>A (chr13-40557795-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002015.4(FOXO1):c.*1254G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 152,276 control chromosomes in the GnomAD database, including 521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 521 hom., cov: 33)

Failed GnomAD Quality Control

Consequence

FOXO1
NM_002015.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.437

Publications

17 publications found

Variant links:

Genes affected

FOXO1 (HGNC:3819): (forkhead box O1) This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. The specific function of this gene has not yet been determined; however, it may play a role in myogenic growth and differentiation. Translocation of this gene with PAX3 has been associated with alveolar rhabdomyosarcoma. [provided by RefSeq, Jul 2008]

FOXO1 links:

ENSG00000288542 (HGNC:):

ENSG00000288542 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 13-40557795-C-T is Benign according to our data. Variant chr13-40557795-C-T is described in ClinVar as Benign. ClinVar VariationId is 1291640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002015.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXO1	NM_002015.4	MANE Select	c.*1254G>A		3_prime_UTR	Exon 3 of 3	NP_002006.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FOXO1	ENST00000379561.6	TSL:1 MANE Select	c.*1254G>A	3_prime_UTR	Exon 3 of 3	ENSP00000368880.4	Q12778
FOXO1	ENST00000962362.1		c.*729G>A	3_prime_UTR	Exon 3 of 3	ENSP00000632421.1
ENSG00000288542	ENST00000636651.2	TSL:5	n.1459+1714G>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0420

AC:

6385

AN:

152158

Hom.:

508

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0129

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0777

Gnomad ASJ

AF:

0.0185

Gnomad EAS

AF:

0.370

Gnomad SAS

AF:

0.0837

Gnomad FIN

AF:

0.0910

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0172

Gnomad OTH

AF:

0.0487

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

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)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.0422

AC:

6420

AN:

152276

Hom.:

521

Cov.:

AF XY:

0.0485

AC XY:

3607

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0129

AC:

536

AN:

41562

American (AMR)

AF:

0.0792

AC:

1212

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0185

AC:

AN:

3468

East Asian (EAS)

AF:

0.369

AC:

1914

AN:

5180

South Asian (SAS)

AF:

0.0833

AC:

402

AN:

4824

European-Finnish (FIN)

AF:

0.0910

AC:

965

AN:

10600

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0172

AC:

1171

AN:

68020

Other (OTH)

AF:

0.0572

AC:

121

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

283

565

848

1130

1413

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<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:

0.0274

Hom.:

557

Bravo

AF:

0.0413

Asia WGS

AF:

0.248

AC:

861

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

2.8

(source)

DANN

Benign

0.27

PhyloP100

0.44

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over