6-108561627-C-T

Variant names:

• chr6-108561627-C-T
• rs111556510
• NM_001455.4:c.419C>T

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.419C>T​(p.Ala140Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0464 in 1,555,948 control chromosomes in the GnomAD database, including 1,924 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.036 (133 hom., cov: 33)
  • Exomes 𝑓: 0.048 (1791 hom.)
• Consequence: FOXO3 NM_001455.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.35
• Publications: 10 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 (MetaRNN=0.0016524792).
• BP6: Variant 6-108561627-C-T is Benign according to our data. Variant chr6-108561627-C-T is described in ClinVar as [Benign]. Clinvar id is 770927.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO3	NM_001455.4	c.419C>T	p.Ala140Val	missense_variant	Exon 1 of 3	ENST00000406360.2	NP_001446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXO3	ENST00000406360.2	c.419C>T	p.Ala140Val	missense_variant	Exon 1 of 3	1	NM_001455.4	ENSP00000385824.1
FOXO3	ENST00000343882.10	c.419C>T	p.Ala140Val	missense_variant	Exon 2 of 4	1		ENSP00000339527.6

Frequencies

GnomAD3 genomes AF: 0.0358 AC: 5440 AN: 151996 Hom.: 134 Cov.: 33

Gnomad AFR AF: 0.00869

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0362

Gnomad ASJ AF: 0.0564

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0536

Gnomad FIN AF: 0.0361

Gnomad MID AF: 0.0994

Gnomad NFE AF: 0.0524

Gnomad OTH AF: 0.0417

GnomAD2 exomes AF: 0.0418 AC: 6200 AN: 148252 AF XY: 0.0453

Gnomad AFR exome AF: 0.00585

Gnomad AMR exome AF: 0.0258

Gnomad ASJ exome AF: 0.0583

Gnomad EAS exome AF: 0.000286

Gnomad FIN exome AF: 0.0370

Gnomad NFE exome AF: 0.0516

Gnomad OTH exome AF: 0.0479

GnomAD4 exome AF: 0.0475 AC: 66700 AN: 1403834 Hom.: 1791 Cov.: 33 AF XY: 0.0480 AC XY: 33299 AN XY: 694326

African (AFR) AF: 0.00768 AC: 242 AN: 31514

American (AMR) AF: 0.0281 AC: 1034 AN: 36788

Ashkenazi Jewish (ASJ) AF: 0.0566 AC: 1400 AN: 24736

East Asian (EAS) AF: 0.000166 AC: 6 AN: 36078

South Asian (SAS) AF: 0.0620 AC: 5028 AN: 81080

European-Finnish (FIN) AF: 0.0364 AC: 1732 AN: 47584

Middle Eastern (MID) AF: 0.0921 AC: 454 AN: 4928

European-Non Finnish (NFE) AF: 0.0501 AC: 54248 AN: 1083066

Other (OTH) AF: 0.0440 AC: 2556 AN: 58060

GnomAD4 genome AF: 0.0357 AC: 5438 AN: 152114 Hom.: 133 Cov.: 33 AF XY: 0.0348 AC XY: 2587 AN XY: 74356

African (AFR) AF: 0.00871 AC: 362 AN: 41564

American (AMR) AF: 0.0361 AC: 553 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0564 AC: 195 AN: 3458

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5158

South Asian (SAS) AF: 0.0535 AC: 258 AN: 4826

European-Finnish (FIN) AF: 0.0361 AC: 383 AN: 10598

Middle Eastern (MID) AF: 0.0966 AC: 28 AN: 290

European-Non Finnish (NFE) AF: 0.0524 AC: 3556 AN: 67902

Other (OTH) AF: 0.0413 AC: 87 AN: 2108

Alfa AF: 0.0332 Hom.: 30

Bravo AF: 0.0336

ESP6500AA AF: 0.00734 AC: 25

ESP6500EA AF: 0.0457 AC: 331

ExAC AF: 0.0310 AC: 3525

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.25	.;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.26	N;N
PhyloP100		1.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.19
Sift	Benign	0.17	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.0010	B;B
Vest4		0.020
ClinPred		0.0089	T
GERP RS		3.0
Varity_R		0.086
gMVP		0.53
Mutation Taster		=88/12	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: rs111556510; hg19: chr6-108882830; COSMIC: COSV59628700;