13-40559996-C-A

Variant names:

• chr13-40559996-C-A
• rs946277208
• NM_002015.4:c.1495G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002015.4(FOXO1):​c.1495G>T​(p.Gly499Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FOXO1 NM_002015.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.86

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]

ENSG00000288542 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3970781).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO1	NM_002015.4	c.1495G>T	p.Gly499Cys	missense_variant	Exon 2 of 3	ENST00000379561.6	NP_002006.2
FOXO1	XM_011535008.3	c.952G>T	p.Gly318Cys	missense_variant	Exon 2 of 3		XP_011533310.1
FOXO1	XM_011535010.3	c.784G>T	p.Gly262Cys	missense_variant	Exon 2 of 3		XP_011533312.1
FOXO1	XM_047430204.1	c.784G>T	p.Gly262Cys	missense_variant	Exon 2 of 3		XP_047286160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXO1	ENST00000379561.6	c.1495G>T	p.Gly499Cys	missense_variant	Exon 2 of 3	1	NM_002015.4	ENSP00000368880.4
ENSG00000288542	ENST00000636651.2	n.972G>T		non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1495G>T (p.G499C) alteration is located in exon 2 (coding exon 2) of the FOXO1 gene. This alteration results from a G to T substitution at nucleotide position 1495, causing the glycine (G) at amino acid position 499 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.51
Sift	Benign	0.11	T
Sift4G	Benign	0.10	T
Polyphen		0.93	P
Vest4		0.38
MutPred		0.40		Gain of catalytic residue at M497 (P = 0);
MVP		0.74
MPC		0.53
ClinPred		0.87	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.25

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: rs946277208; hg19: chr13-41134133;