13-40559613-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002015.4(FOXO1):c.1878T>A(p.Asp626Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXO1 NM_002015.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.116

Genes affected

FOXO1 (HGNC:3819): (forkhead box O1) This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. The specific function of this gene has not yet been determined; however, it may play a role in myogenic growth and differentiation. Translocation of this gene with PAX3 has been associated with alveolar rhabdomyosarcoma. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17133558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXO1	NM_002015.4	c.1878T>A	p.Asp626Glu	missense_variant	2/3	ENST00000379561.6
FOXO1	XM_011535008.3	c.1335T>A	p.Asp445Glu	missense_variant	2/3
FOXO1	XM_011535010.3	c.1167T>A	p.Asp389Glu	missense_variant	2/3
FOXO1	XM_047430204.1	c.1167T>A	p.Asp389Glu	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXO1	ENST00000379561.6	c.1878T>A	p.Asp626Glu	missense_variant	2/3	1	NM_002015.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2023

The c.1878T>A (p.D626E) alteration is located in exon 2 (coding exon 2) of the FOXO1 gene. This alteration results from a T to A substitution at nucleotide position 1878, causing the aspartic acid (D) at amino acid position 626 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	11
Dann	Benign	0.89
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.33	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.24
Sift	Benign	0.099	T
Sift4G	Benign	0.42	T
Polyphen		0.0020	B
Vest4		0.10
MutPred		0.39		Gain of catalytic residue at L622 (P = 0.0013);
MVP		0.61
MPC		0.21
ClinPred		0.075	T
GERP RS		-7.2
Varity_R		0.089
gMVP		0.31

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-41133750;