chrX-71101060-A-C

Variant names:

• chrX-71101060-A-C
• NM_005938.4:c.830A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005938.4(FOXO4):​c.830A>C​(p.Glu277Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: FOXO4 NM_005938.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.88
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005938.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXO4	NM_005938.4	MANE Select	c.830A>C	p.Glu277Ala	missense	Exon 2 of 3	NP_005929.2	P98177-1
	FOXO4	NM_001170931.2		c.665A>C	p.Glu222Ala	missense	Exon 3 of 4	NP_001164402.1	P98177-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXO4	ENST00000374259.8	TSL:1 MANE Select	c.830A>C	p.Glu277Ala	missense	Exon 2 of 3	ENSP00000363377.3	P98177-1
	FOXO4	ENST00000341558.4	TSL:5	c.665A>C	p.Glu222Ala	missense	Exon 3 of 4	ENSP00000342209.3	P98177-2
	FOXO4	ENST00000464598.1	TSL:2	n.*217A>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.9
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.023	D
Sift4G	Benign	0.086	T
Polyphen		1.0	D
Vest4		0.25
MutPred		0.18		Gain of MoRF binding (P = 0.1159)
MVP		0.95
MPC		0.99
ClinPred		0.93	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.39
gMVP		0.60
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

hg19: chrX-70320910;