Genetic Variant NM_001455.4:c.419C>T (chr6-108561627-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001455.4(FOXO3):c.419C>T(p.Ala140Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0464 in 1,555,948 control chromosomes in the GnomAD database, including 1,924 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.036 ( 133 hom., cov: 33)

Exomes 𝑓: 0.048 ( 1791 hom. )

Consequence

FOXO3
NM_001455.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.35

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 made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016524792).

BP6

Variant 6-108561627-C-T is Benign according to our data. Variant chr6-108561627-C-T is described in ClinVar as [Benign]. Clinvar id is 770927.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO3	NM_001455.4 link	c.419C>T	p.Ala140Val	missense_variant	Exon 1 of 3	ENST00000406360.2	NP_001446.1	O43524-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXO3	ENST00000406360.2 link	c.419C>T	p.Ala140Val	missense_variant	Exon 1 of 3	1	NM_001455.4	ENSP00000385824.1		O43524-1
FOXO3	ENST00000343882.10 link	c.419C>T	p.Ala140Val	missense_variant	Exon 2 of 4	1		ENSP00000339527.6		O43524-1

Frequencies

GnomAD3 genomes

AF:

0.0358

AC:

5440

AN:

151996

Hom.:

134

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00869

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.0362

Gnomad ASJ

AF:

0.0564

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.0536

Gnomad FIN

AF:

0.0361

Gnomad MID

AF:

0.0994

Gnomad NFE

AF:

0.0524

Gnomad OTH

AF:

0.0417

GnomAD3 exomes

AF:

0.0418

AC:

6200

AN:

148252

Hom.:

169

AF XY:

0.0453

AC XY:

3686

AN XY:

81412

show subpopulations

Gnomad AFR exome

AF:

0.00585

Gnomad AMR exome

AF:

0.0258

Gnomad ASJ exome

AF:

0.0583

Gnomad EAS exome

AF:

0.000286

Gnomad SAS exome

AF:

0.0598

Gnomad FIN exome

AF:

0.0370

Gnomad NFE exome

AF:

0.0516

Gnomad OTH exome

AF:

0.0479

GnomAD4 exome

AF:

0.0475

AC:

66700

AN:

1403834

Hom.:

1791

Cov.:

AF XY:

0.0480

AC XY:

33299

AN XY:

694326

show subpopulations

Gnomad4 AFR exome

AF:

0.00768

Gnomad4 AMR exome

AF:

0.0281

Gnomad4 ASJ exome

AF:

0.0566

Gnomad4 EAS exome

AF:

0.000166

Gnomad4 SAS exome

AF:

0.0620

Gnomad4 FIN exome

AF:

0.0364

Gnomad4 NFE exome

AF:

0.0501

Gnomad4 OTH exome

AF:

0.0440

GnomAD4 genome

AF:

0.0357

AC:

5438

AN:

152114

Hom.:

133

Cov.:

AF XY:

0.0348

AC XY:

2587

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00871

Gnomad4 AMR

AF:

0.0361

Gnomad4 ASJ

AF:

0.0564

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.0535

Gnomad4 FIN

AF:

0.0361

Gnomad4 NFE

AF:

0.0524

Gnomad4 OTH

AF:

0.0413

Alfa

AF:

0.0334

Hom.:

Bravo

AF:

0.0336

ESP6500AA

AF:

0.00734

AC:

ESP6500EA

AF:

0.0457

AC:

331

ExAC

AF:

0.0310

AC:

3525

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.25

.;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.26

N;N

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.19

Sift

Benign

0.17

T;T

Sift4G

Benign

0.11

T;T

Polyphen

0.0010

B;B

Vest4

0.020

ClinPred

0.0089

GERP RS

3.0

Varity_R

0.086

gMVP

0.53

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