chr6-108561636-G-T

Variant names:

• chr6-108561636-G-T
• rs756842922
• NM_001455.4:c.428G>T

Variant summary

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

The NM_001455.4(FOXO3):​c.428G>T​(p.Gly143Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000312 in 1,569,290 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 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: FOXO3 NM_001455.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49
• 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=0.13963944).
• BS2: High AC in GnomAd4 at 12 AD gene.

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.428G>T	p.Gly143Val	missense	Exon 1 of 3	NP_001446.1	O43524-1
	FOXO3	NM_201559.3		c.428G>T	p.Gly143Val	missense	Exon 2 of 4	NP_963853.1	O43524-1
	FOXO3	NM_001415150.1		c.428G>T	p.Gly143Val	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.428G>T	p.Gly143Val	missense	Exon 1 of 3	ENSP00000385824.1	O43524-1
	FOXO3	ENST00000343882.10	TSL:1	c.428G>T	p.Gly143Val	missense	Exon 2 of 4	ENSP00000339527.6	O43524-1
	FOXO3	ENST00000898147.1		c.428G>T	p.Gly143Val	missense	Exon 2 of 4	ENSP00000568206.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

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: 0.0000610 AC: 10 AN: 163918 AF XY: 0.0000443

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000390

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000261 AC: 37 AN: 1417172 Hom.: 0 Cov.: 32 AF XY: 0.0000199 AC XY: 14 AN XY: 701982

African (AFR) AF: 0.000188 AC: 6 AN: 31944

American (AMR) AF: 0.000260 AC: 10 AN: 38490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25066

East Asian (EAS) AF: 0.00 AC: 0 AN: 36734

South Asian (SAS) AF: 0.00 AC: 0 AN: 82364

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5134

European-Non Finnish (NFE) AF: 0.0000119 AC: 13 AN: 1090172

Other (OTH) AF: 0.000137 AC: 8 AN: 58556

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.000785 AC: 12 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.00000851 AC: 1

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	0.075
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.056
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.60	N
PhyloP100		1.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.89	N
REVEL	Uncertain	0.39
Sift	Benign	0.072	T
Sift4G	Benign	0.25	T
Polyphen		0.23	B
Vest4		0.060
MutPred		0.37		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.90
ClinPred		0.046	T
GERP RS		2.9
Varity_R		0.12
gMVP		0.62
Mutation Taster		=85/15	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: rs756842922; hg19: chr6-108882839;