Variant chr13-40559873-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_002015.4(FOXO1):c.1618C>T(p.Pro540Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

FOXO1
NM_002015.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.27

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07968569).

BP6

Variant 13-40559873-G-A is Benign according to our data. Variant chr13-40559873-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3279639.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FOXO1	NM_002015.4 linkuse as main transcript	c.1618C>T	p.Pro540Ser	missense_variant	2/3	ENST00000379561.6	NP_002006.2
FOXO1	XM_011535008.3 linkuse as main transcript	c.1075C>T	p.Pro359Ser	missense_variant	2/3		XP_011533310.1
FOXO1	XM_011535010.3 linkuse as main transcript	c.907C>T	p.Pro303Ser	missense_variant	2/3		XP_011533312.1
FOXO1	XM_047430204.1 linkuse as main transcript	c.907C>T	p.Pro303Ser	missense_variant	2/3		XP_047286160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXO1	ENST00000379561.6 linkuse as main transcript	c.1618C>T	p.Pro540Ser	missense_variant	2/3	1	NM_002015.4	ENSP00000368880	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251126

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135686

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000406

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.26

CADD

Benign

3.9

DANN

Benign

0.21

DEOGEN2

Benign

0.35

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.80

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.72

M_CAP

Benign

0.038

MetaRNN

Benign

0.080

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.94

MutationTaster

Benign

0.96

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.29

REVEL

Benign

0.20

Sift

Benign

0.93

Sift4G

Benign

1.0

Polyphen

0.0050

Vest4

0.16

MutPred

0.30

Gain of catalytic residue at R537 (P = 0.0112);

MVP

0.46

MPC

0.23

ClinPred

0.037

GERP RS

2.9

Varity_R

0.044

gMVP

0.29

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over