6-108561639-C-T

Variant names:

• chr6-108561639-C-T
• rs778623754
• NM_001455.4:c.431C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001455.4(FOXO3):​c.431C>T​(p.Ser144Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,421,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S144C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FOXO3 NM_001455.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32524812).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001455.4. 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
	FOXO3	NM_001455.4	MANE Select	c.431C>T	p.Ser144Phe	missense	Exon 1 of 3	NP_001446.1	O43524-1
	FOXO3	NM_201559.3		c.431C>T	p.Ser144Phe	missense	Exon 2 of 4	NP_963853.1	O43524-1
	FOXO3	NM_001415150.1		c.431C>T	p.Ser144Phe	missense	Exon 2 of 3	NP_001402079.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXO3	ENST00000406360.2	TSL:1 MANE Select	c.431C>T	p.Ser144Phe	missense	Exon 1 of 3	ENSP00000385824.1	O43524-1
	FOXO3	ENST00000343882.10	TSL:1	c.431C>T	p.Ser144Phe	missense	Exon 2 of 4	ENSP00000339527.6	O43524-1
	FOXO3	ENST00000898147.1		c.431C>T	p.Ser144Phe	missense	Exon 2 of 4	ENSP00000568206.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1421904 Hom.: 0 Cov.: 32 AF XY: 0.00000142 AC XY: 1 AN XY: 704708

African (AFR) AF: 0.00 AC: 0 AN: 32028

American (AMR) AF: 0.00 AC: 0 AN: 39046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 37122

South Asian (SAS) AF: 0.0000242 AC: 2 AN: 82736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5256

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092652

Other (OTH) AF: 0.00 AC: 0 AN: 58730

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.081
Eigen_PC	Benign	-0.019
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.087	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.29
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.015	D
Polyphen		0.53	P
Vest4		0.12
MutPred		0.34		Loss of glycosylation at S144 (P = 5e-04)
MVP		0.93
ClinPred		0.71	D
GERP RS		3.9
Varity_R		0.22
gMVP		0.73
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs778623754; hg19: chr6-108882842;