6-108561639-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001415139.1(FOXO3):​c.-385C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000159 in 1,574,030 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: FOXO3 NM_001415139.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22894385).
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001415139.1. 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>G	p.Ser144Cys	missense	Exon 1 of 3	NP_001446.1	O43524-1
	FOXO3	NM_001415139.1		c.-385C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_001402068.1
	FOXO3	NM_001415140.1		c.-254C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	NP_001402069.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXO3	ENST00000406360.2	TSL:1 MANE Select	c.431C>G	p.Ser144Cys	missense	Exon 1 of 3	ENSP00000385824.1	O43524-1
	FOXO3	ENST00000343882.10	TSL:1	c.431C>G	p.Ser144Cys	missense	Exon 2 of 4	ENSP00000339527.6	O43524-1
	FOXO3	ENST00000898147.1		c.431C>G	p.Ser144Cys	missense	Exon 2 of 4	ENSP00000568206.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000117 AC: 2 AN: 170344 AF XY: 0.0000213

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000142

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.0000162 AC: 23 AN: 1421904 Hom.: 0 Cov.: 32 AF XY: 0.0000170 AC XY: 12 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: 0.00 AC: 0 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: 0.0000183 AC: 20 AN: 1092652

Other (OTH) AF: 0.0000511 AC: 3 AN: 58730

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000254 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.094
Eigen_PC	Benign	-0.024
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	-0.073	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.020	D
Polyphen		0.53	P
Vest4		0.080
MutPred		0.37		Loss of glycosylation at S144 (P = 5e-04)
MVP		0.90
ClinPred		0.27	T
GERP RS		3.9
Varity_R		0.23
gMVP		0.79
Mutation Taster		=75/25	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;