Genetic Variant NM_005938.4:c.29C>G (chrX-71096557-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005938.4(FOXO4):c.29C>G(p.Thr10Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,095,096 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

FOXO4
NM_005938.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.472

Publications

0 publications found

Variant links:

Genes affected

FOXO4 (HGNC:7139): (forkhead box O4) This gene encodes a member of the O class of winged helix/forkhead transcription factor family. Proteins encoded by this class are regulated by factors involved in growth and differentiation indicating they play a role in these processes. A translocation involving this gene on chromosome X and the homolog of the Drosophila trithorax gene, encoding a DNA binding protein, located on chromosome 11 is associated with leukemia. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

FOXO4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07764682).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO4	NM_005938.4 link	c.29C>G	p.Thr10Arg	missense_variant	Exon 1 of 3	ENST00000374259.8	NP_005929.2	P98177-1
FOXO4	NM_001170931.2 link	c.29C>G	p.Thr10Arg	missense_variant	Exon 1 of 4		NP_001164402.1	P98177-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FOXO4	ENST00000374259.8 link	c.29C>G	p.Thr10Arg	missense_variant	Exon 1 of 3	1	NM_005938.4	ENSP00000363377.3	P98177-1
FOXO4	ENST00000341558.4 link	c.29C>G	p.Thr10Arg	missense_variant	Exon 1 of 4	5		ENSP00000342209.3	P98177-2
FOXO4	ENST00000466874.1 link	n.305C>G		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1095096

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

360840

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26350

American (AMR)

AF:

0.00

AC:

AN:

34898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19308

East Asian (EAS)

AF:

0.00

AC:

AN:

30104

South Asian (SAS)

AF:

0.00

AC:

AN:

53547

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40211

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4127

European-Non Finnish (NFE)

AF:

0.00000357

AC:

AN:

840567

Other (OTH)

AF:

0.00

AC:

AN:

45984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.29C>G (p.T10R) alteration is located in exon 1 (coding exon 1) of the FOXO4 gene. This alteration results from a C to G substitution at nucleotide position 29, causing the threonine (T) at amino acid position 10 to be replaced by an arginine (R). 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

0.082

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.40

T;.

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.078

T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.69

N;N

PhyloP100

0.47

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.92

N;N

REVEL

Benign

0.23

Sift

Benign

0.15

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.0

B;B

Vest4

0.099

MutPred

0.11

Loss of glycosylation at T10 (P = 0.014);Loss of glycosylation at T10 (P = 0.014);

MVP

0.64

MPC

0.39

ClinPred

0.079

GERP RS

2.1

PromoterAI

-0.032

Neutral

(source)

Varity_R

0.26

gMVP

0.42

Mutation Taster

=82/18

polymorphism

(source)

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

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NM_005938.4:c.29C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over