6-108561621-C-T

Variant names:

• chr6-108561621-C-T
• rs767626656
• NM_001455.4:c.413C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001415139.1(FOXO3):​c.-403C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXO3 NM_001415139.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.249
• Publications: 0 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.122706205).

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.413C>T	p.Pro138Leu	missense	Exon 1 of 3	NP_001446.1	O43524-1
	FOXO3	NM_001415139.1		c.-403C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_001402068.1
	FOXO3	NM_001415140.1		c.-272C>T		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.413C>T	p.Pro138Leu	missense	Exon 1 of 3	ENSP00000385824.1	O43524-1
	FOXO3	ENST00000343882.10	TSL:1	c.413C>T	p.Pro138Leu	missense	Exon 2 of 4	ENSP00000339527.6	O43524-1
	FOXO3	ENST00000898147.1		c.413C>T	p.Pro138Leu	missense	Exon 2 of 4	ENSP00000568206.1

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 344 AN: 149474 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00804

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00147

GnomAD2 exomes AF: 0.0000788 AC: 11 AN: 139624 AF XY: 0.0000916

Gnomad AFR exome AF: 0.00130

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: 0.00

Gnomad OTH exome AF: 0.000258

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000176 AC: 246 AN: 1395578 Hom.: 0 Cov.: 32 AF XY: 0.000139 AC XY: 96 AN XY: 689784

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00523 AC: 155 AN: 29664

American (AMR) AF: 0.0000557 AC: 2 AN: 35904

Ashkenazi Jewish (ASJ) AF: 0.0000408 AC: 1 AN: 24482

East Asian (EAS) AF: 0.00 AC: 0 AN: 35874

South Asian (SAS) AF: 0.0000249 AC: 2 AN: 80452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47094

Middle Eastern (MID) AF: 0.000415 AC: 2 AN: 4822

European-Non Finnish (NFE) AF: 0.0000630 AC: 68 AN: 1079882

Other (OTH) AF: 0.000279 AC: 16 AN: 57404

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00232 AC: 347 AN: 149584 Hom.: 0 Cov.: 33 AF XY: 0.00232 AC XY: 170 AN XY: 73124

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00810 AC: 318 AN: 39268

American (AMR) AF: 0.00105 AC: 16 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67854

Other (OTH) AF: 0.00145 AC: 3 AN: 2068

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00269 Hom.: 0

ExAC AF: 0.0000178 AC: 2

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	0.090
BayesDel_addAF	Benign	-0.0030	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.25
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.27
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.020	D
Polyphen		0.0050	B
Vest4		0.075
MutPred		0.38		Loss of glycosylation at P138 (P = 0.0238)
MVP		0.89
ClinPred		0.023	T
GERP RS		3.9
Varity_R		0.14
gMVP		0.34
Mutation Taster		=88/12	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: rs767626656; hg19: chr6-108882824;