X-71096676-G-A

Position:

• chrX-71096676-G-A

Variant summary

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

The NM_005938.4(FOXO4):​c.148G>A​(p.Val50Met) 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. 12/20 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: 22)
• Consequence: FOXO4 NM_005938.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

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=0.17128819).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXO4	NM_005938.4	c.148G>A	p.Val50Met	missense_variant	1/3	ENST00000374259.8	NP_005929.2
FOXO4	NM_001170931.2	c.148G>A	p.Val50Met	missense_variant	1/4		NP_001164402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXO4	ENST00000374259.8	c.148G>A	p.Val50Met	missense_variant	1/3	1	NM_005938.4	ENSP00000363377.3
FOXO4	ENST00000341558.3	c.148G>A	p.Val50Met	missense_variant	1/4	5		ENSP00000342209.3
FOXO4	ENST00000466874.1	n.424G>A		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000113

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

Oct 01, 2024

The c.148G>A (p.V50M) alteration is located in exon 1 (coding exon 1) of the FOXO4 gene. This alteration results from a G to A substitution at nucleotide position 148, causing the valine (V) at amino acid position 50 to be replaced by a methionine (M). 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	0.084
BayesDel_addAF	Benign	0.0064	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.4	L;L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.82	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.11	T;T
Sift4G	Benign	0.10	T;T
Polyphen		0.080	B;P
Vest4		0.22
MVP		0.88
MPC		0.48
ClinPred		0.28	T
GERP RS		3.3
Varity_R		0.14
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1381657176; hg19: chrX-70316526;