X-71096725-C-G

Variant names:

• chrX-71096725-C-G
• rs774656186
• NM_005938.4:c.197C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005938.4(FOXO4):​c.197C>G​(p.Pro66Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000747 in 1,204,439 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 3 hem.)
• Consequence: FOXO4 NM_005938.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.652
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1901724).
• BS2: High Hemizygotes in GnomAdExome4 at 3 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.197C>G	p.Pro66Arg	missense	Exon 1 of 3	NP_005929.2	P98177-1
	FOXO4	NM_001170931.2		c.171+26C>G		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.197C>G	p.Pro66Arg	missense	Exon 1 of 3	ENSP00000363377.3	P98177-1
	FOXO4	ENST00000341558.4	TSL:5	c.171+26C>G		intron	N/A	ENSP00000342209.3	P98177-2
	FOXO4	ENST00000466874.1	TSL:3	n.447+26C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112267 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: 0.000281

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: 0.0000244 AC: 4 AN: 163927 AF XY: 0.0000186

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000321

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000732 AC: 8 AN: 1092172 Hom.: 0 Cov.: 31 AF XY: 0.00000837 AC XY: 3 AN XY: 358410

African (AFR) AF: 0.00 AC: 0 AN: 26259

American (AMR) AF: 0.00 AC: 0 AN: 34653

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19255

East Asian (EAS) AF: 0.000234 AC: 7 AN: 29854

South Asian (SAS) AF: 0.00 AC: 0 AN: 53151

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40005

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4111

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839069

Other (OTH) AF: 0.0000218 AC: 1 AN: 45815

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112267 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34407

African (AFR) AF: 0.00 AC: 0 AN: 30942

American (AMR) AF: 0.00 AC: 0 AN: 10701

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.000281 AC: 1 AN: 3559

South Asian (SAS) AF: 0.00 AC: 0 AN: 2718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53106

Other (OTH) AF: 0.00 AC: 0 AN: 1519

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000166 AC: 2

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	0.099
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Uncertain	0.73	D
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.1	L
PhyloP100		0.65
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.23
Sift	Benign	0.036	D
Sift4G	Benign	0.076	T
Polyphen		0.31	B
Vest4		0.080
MutPred		0.31		Loss of glycosylation at S71 (P = 0.1023)
MVP		0.78
MPC		1.1
ClinPred		0.093	T
GERP RS		4.3
PromoterAI		0.025	Neutral
Varity_R		0.42
gMVP		0.63
Mutation Taster		=73/27	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: rs774656186; hg19: chrX-70316575;