chrX-71096557-C-G

Position:

• chrX-71096557-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: FOXO4 NM_005938.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.472

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 (HGNC:):

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=0.07764682).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXO4	NM_005938.4	c.29C>G	p.Thr10Arg	missense_variant	1/3	ENST00000374259.8	NP_005929.2
FOXO4	NM_001170931.2	c.29C>G	p.Thr10Arg	missense_variant	1/4		NP_001164402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXO4	ENST00000374259.8	c.29C>G	p.Thr10Arg	missense_variant	1/3	1	NM_005938.4	ENSP00000363377.3
FOXO4	ENST00000341558.3	c.29C>G	p.Thr10Arg	missense_variant	1/4	5		ENSP00000342209.3
FOXO4	ENST00000466874.1	n.305C>G		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1095096 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 1 AN XY: 360840

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000357

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

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

Jul 14, 2024

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	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.40	T;.
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Benign	0.42	T
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	T
GERP RS		2.1
Varity_R		0.26
gMVP		0.42

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-70316407;