X-71096838-C-A

Variant names:

• chrX-71096838-C-A
• NM_005938.4:c.310C>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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66

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]

ACMG classification

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
FOXO4	NM_005938.4	c.310C>A	p.Gln104Lys	missense_variant	Exon 1 of 3	ENST00000374259.8	NP_005929.2
FOXO4	NM_001170931.2	c.172-27C>A		intron_variant	Intron 1 of 3		NP_001164402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXO4	ENST00000374259.8	c.310C>A	p.Gln104Lys	missense_variant	Exon 1 of 3	1	NM_005938.4	ENSP00000363377.3
FOXO4	ENST00000341558.3	c.172-27C>A		intron_variant	Intron 1 of 3	5		ENSP00000342209.3
FOXO4	ENST00000466874.1	n.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

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;