chr6-108561319-G-T

Variant names:

• chr6-108561319-G-T
• NM_001455.4:c.111G>T

Variant summary

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

The NM_001455.4(FOXO3):​c.111G>T​(p.Arg37Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FOXO3 NM_001455.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.374

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]

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=0.3843007).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO3	NM_001455.4	c.111G>T	p.Arg37Ser	missense_variant	Exon 1 of 3	ENST00000406360.2	NP_001446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXO3	ENST00000406360.2	c.111G>T	p.Arg37Ser	missense_variant	Exon 1 of 3	1	NM_001455.4	ENSP00000385824.1
FOXO3	ENST00000343882.10	c.111G>T	p.Arg37Ser	missense_variant	Exon 2 of 4	1		ENSP00000339527.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.111G>T (p.R37S) alteration is located in exon 1 (coding exon 1) of the FOXO3 gene. This alteration results from a G to T substitution at nucleotide position 111, causing the arginine (R) at amino acid position 37 to be replaced by a serine (S). 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	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.58	D
LIST_S2	Pathogenic	0.97	.;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.049	B;B
Vest4		0.20
MutPred		0.26		Gain of phosphorylation at R37 (P = 0.0222);Gain of phosphorylation at R37 (P = 0.0222);
MVP		0.90
ClinPred		0.89	D
GERP RS		3.1
Varity_R		0.78
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-108882522;