X-71096838-C-A

Variant summary

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

The NM_005938.4(FOXO4):​c.310C>A​(p.Gln104Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Consequence

FOXO4
NM_005938.4 missense

Scores

3
11
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.66
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FOXO4NM_005938.4 linkc.310C>A p.Gln104Lys missense_variant Exon 1 of 3 ENST00000374259.8 NP_005929.2 P98177-1
FOXO4NM_001170931.2 linkc.172-27C>A intron_variant Intron 1 of 3 NP_001164402.1 P98177-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FOXO4ENST00000374259.8 linkc.310C>A p.Gln104Lys missense_variant Exon 1 of 3 1 NM_005938.4 ENSP00000363377.3 P98177-1
FOXO4ENST00000341558.3 linkc.172-27C>A intron_variant Intron 1 of 3 5 ENSP00000342209.3 P98177-2
FOXO4ENST00000466874.1 linkn.448-23C>A intron_variant Intron 1 of 2 3

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 26, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.310C>A (p.Q104K) alteration is located in exon 1 (coding exon 1) of the FOXO4 gene. This alteration results from a C to A substitution at nucleotide position 310, causing the glutamine (Q) at amino acid position 104 to be replaced by a lysine (K). 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
Uncertain
0.40
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.50
D
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.90
D
M_CAP
Uncertain
0.18
D
MetaRNN
Uncertain
0.58
D
MetaSVM
Uncertain
0.70
D
MutationAssessor
Benign
0.57
N
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-1.3
N
REVEL
Pathogenic
0.74
Sift
Uncertain
0.011
D
Sift4G
Uncertain
0.025
D
Polyphen
0.40
B
Vest4
0.51
MutPred
0.74
Loss of catalytic residue at Q104 (P = 0.0045);
MVP
0.94
MPC
1.2
ClinPred
0.82
D
GERP RS
4.7
Varity_R
0.59
gMVP
0.94

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: chrX-70316688; API