X-71096661-T-C

Variant names:

• chrX-71096661-T-C
• rs752307791
• NM_005938.4:c.133T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005938.4(FOXO4):​c.133T>C​(p.Ser45Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,097,005 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000012 (0 hom. 4 hem.)
• Consequence: FOXO4 NM_005938.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.17
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02696976).
• BP6: Variant X-71096661-T-C is Benign according to our data. Variant chrX-71096661-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 4026450.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO4	NM_005938.4	c.133T>C	p.Ser45Pro	missense_variant	Exon 1 of 3	ENST00000374259.8	NP_005929.2
FOXO4	NM_001170931.2	c.133T>C	p.Ser45Pro	missense_variant	Exon 1 of 4		NP_001164402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXO4	ENST00000374259.8	c.133T>C	p.Ser45Pro	missense_variant	Exon 1 of 3	1	NM_005938.4	ENSP00000363377.3
FOXO4	ENST00000341558.4	c.133T>C	p.Ser45Pro	missense_variant	Exon 1 of 4	5		ENSP00000342209.3
FOXO4	ENST00000466874.1	n.409T>C		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000626 AC: 11 AN: 175633 AF XY: 0.0000479

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000407

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000119 AC: 13 AN: 1097005 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 4 AN XY: 362463

African (AFR) AF: 0.00 AC: 0 AN: 26383

American (AMR) AF: 0.000342 AC: 12 AN: 35109

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19356

East Asian (EAS) AF: 0.00 AC: 0 AN: 30131

South Asian (SAS) AF: 0.00 AC: 0 AN: 53919

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40391

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841564

Other (OTH) AF: 0.0000217 AC: 1 AN: 46016

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

May 26, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.0
DANN	Benign	0.87
DEOGEN2	Benign	0.37	T;.
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.027	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	-0.34	N;N
PhyloP100		-1.2
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.26	N;N
REVEL	Benign	0.22
Sift	Benign	0.19	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.0	B;B
Vest4		0.044
MutPred		0.20		Gain of catalytic residue at P44 (P = 0.012);Gain of catalytic residue at P44 (P = 0.012);
MVP		0.51
MPC		0.43
ClinPred		0.050	T
GERP RS		-2.8
PromoterAI		0.021	Neutral
Varity_R		0.11
gMVP		0.25
Mutation Taster		=88/12	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: rs752307791; hg19: chrX-70316511;