X-71096776-G-A

Variant names:

• chrX-71096776-G-A
• rs756310763
• NM_005938.4:c.248G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005938.4(FOXO4):​c.248G>A​(p.Gly83Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,197,552 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 1 hem.)
• Consequence: FOXO4 NM_005938.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016977668).
• BS2: High Hemizygotes in GnomAd4 at 2 gene

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.248G>A	p.Gly83Glu	missense	Exon 1 of 3	NP_005929.2	P98177-1
	FOXO4	NM_001170931.2		c.171+77G>A		intron	N/A	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.248G>A	p.Gly83Glu	missense	Exon 1 of 3	ENSP00000363377.3	P98177-1
	FOXO4	ENST00000341558.4	TSL:5	c.171+77G>A		intron	N/A	ENSP00000342209.3	P98177-2
	FOXO4	ENST00000466874.1	TSL:3	n.447+77G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000446 AC: 5 AN: 112149 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00142

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000929 AC: 14 AN: 150671 AF XY: 0.000107

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00122

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000101 AC: 11 AN: 1085351 Hom.: 0 Cov.: 31 AF XY: 0.00000282 AC XY: 1 AN XY: 354013

African (AFR) AF: 0.00 AC: 0 AN: 26061

American (AMR) AF: 0.00 AC: 0 AN: 33601

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19090

East Asian (EAS) AF: 0.000339 AC: 10 AN: 29501

South Asian (SAS) AF: 0.00 AC: 0 AN: 52533

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39587

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4095

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 835379

Other (OTH) AF: 0.0000220 AC: 1 AN: 45504

GnomAD4 genome AF: 0.0000357 AC: 4 AN: 112201 Hom.: 0 Cov.: 23 AF XY: 0.0000581 AC XY: 2 AN XY: 34395

African (AFR) AF: 0.00 AC: 0 AN: 31007

American (AMR) AF: 0.00 AC: 0 AN: 10719

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00114 AC: 4 AN: 3509

South Asian (SAS) AF: 0.00 AC: 0 AN: 2715

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6125

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53039

Other (OTH) AF: 0.00 AC: 0 AN: 1540

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000919 AC: 11

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Benign	0.57
DEOGEN2	Uncertain	0.58	D
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	-0.69	N
PhyloP100		1.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.076
MutPred		0.37		Loss of MoRF binding (P = 0.1006)
MVP		0.57
MPC		0.45
ClinPred		0.038	T
GERP RS		1.8
PromoterAI		-0.0030	Neutral
Varity_R		0.19
gMVP		0.74
Mutation Taster		=96/4	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

dbSNP: rs756310763; hg19: chrX-70316626;