6-108682118-T-C

Variant names:

• chr6-108682118-T-C
• rs4946936
• NM_001455.4:c.*2326T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001455.4(FOXO3):​c.*2326T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 152,522 control chromosomes in the GnomAD database, including 26,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.54 (26381 hom., cov: 32)
  • Exomes 𝑓: 0.63 (71 hom.)
• Consequence: FOXO3 NM_001455.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.552
• Publications: 54 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-108682118-T-C is Benign according to our data. Variant chr6-108682118-T-C is described in ClinVar as Benign. ClinVar VariationId is 1272154.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXO3	NM_001455.4	MANE Select	c.*2326T>C		3_prime_UTR	Exon 3 of 3	NP_001446.1
	FOXO3	NM_201559.3		c.*2326T>C		3_prime_UTR	Exon 4 of 4	NP_963853.1
	FOXO3	NM_001415139.1		c.*2326T>C		3_prime_UTR	Exon 3 of 3	NP_001402068.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXO3	ENST00000406360.2	TSL:1 MANE Select	c.*2326T>C		3_prime_UTR	Exon 3 of 3	ENSP00000385824.1
	FOXO3	ENST00000343882.10	TSL:1	c.*2326T>C		3_prime_UTR	Exon 4 of 4	ENSP00000339527.6

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82188 AN: 152006 Hom.: 26382 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.813

Gnomad AMR AF: 0.639

Gnomad ASJ AF: 0.750

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.530

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.568

GnomAD4 exome AF: 0.628 AC: 250 AN: 398 Hom.: 71 Cov.: 0 AF XY: 0.633 AC XY: 152 AN XY: 240

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.630 AC: 247 AN: 392

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.540 AC: 82204 AN: 152124 Hom.: 26381 Cov.: 32 AF XY: 0.540 AC XY: 40125 AN XY: 74356

African (AFR) AF: 0.171 AC: 7080 AN: 41494

American (AMR) AF: 0.639 AC: 9766 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 2600 AN: 3468

East Asian (EAS) AF: 0.710 AC: 3677 AN: 5176

South Asian (SAS) AF: 0.531 AC: 2556 AN: 4814

European-Finnish (FIN) AF: 0.622 AC: 6576 AN: 10580

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.704 AC: 47844 AN: 67988

Other (OTH) AF: 0.570 AC: 1206 AN: 2114

Alfa AF: 0.612 Hom.: 9568

Bravo AF: 0.529

Asia WGS AF: 0.558 AC: 1942 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 15, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25060657)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.8
DANN	Benign	0.74
PhyloP100		0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs4946936; hg19: chr6-109003321; COSMIC: COSV59626116; COSMIC: COSV59626116;