X-49251440-C-T

Variant names:

• chrX-49251440-C-T
• rs1057520529
• NM_014009.4:c.1190G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_014009.4(FOXP3):​c.1190G>A​(p.Arg397Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,098,155 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R397W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: FOXP3 NM_014009.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.95
• Publications: 14 publications found

Genes affected

FOXP3 (HGNC:6106): (forkhead box P3) The protein encoded by this gene is a member of the forkhead/winged-helix family of transcriptional regulators. Defects in this gene are the cause of immunodeficiency polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), also known as X-linked autoimmunity-immunodeficiency syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

FOXP3 Gene-Disease associations (from GenCC):

• immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-49251441-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-49251440-C-T is Pathogenic according to our data. Variant chrX-49251440-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 379222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP3	NM_014009.4	c.1190G>A	p.Arg397Gln	missense_variant	Exon 12 of 12	ENST00000376207.10	NP_054728.2
FOXP3	NM_001114377.2	c.1085G>A	p.Arg362Gln	missense_variant	Exon 11 of 11		NP_001107849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP3	ENST00000376207.10	c.1190G>A	p.Arg397Gln	missense_variant	Exon 12 of 12	1	NM_014009.4	ENSP00000365380.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098155 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363519

African (AFR) AF: 0.00 AC: 0 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.00 AC: 0 AN: 54129

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40509

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

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 842102

Other (OTH) AF: 0.00 AC: 0 AN: 46096

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

May 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious on protein structure/function as well as an effect on splicing; Located in the forkhead DNA binding domain (Consonni et al., 2021); This variant is associated with the following publications: (PMID: 30443250, 29312905, 23534934, 32963853, 32441320, 27484032, 30755392, 20650610, 32888943, 33614561) -

Nov 19, 2018

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2, PM5, PM6, PS4 -

Insulin-dependent diabetes mellitus secretory diarrhea syndrome Pathogenic:3

Dec 25, 2024

Obstetrics Unit, Tongji Hospital, Huazhong University of Science and Technology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FOXP3:NM_014009.4:exon12:c.1190G>A:p.R397Q mutation: possibly pathogenic (PM2+PS4_Moderate+PP3+PM6_Supporting) Moderate evidence of pathogenicity PM2: This variant is not found in the reference population 1000 Genomes (1000G), the Human Exome Database (ExAC) and the Population Genome Mutation Frequency Database (gnomAD); Moderate evidence of pathogenicity PS4_Moderate: The literature reported that the mutation was detected in a total of several (6-14) patients [PMID:20650610;23534934;27484032;29312905;30443250;30755392;32441320;32888943]; Supports evidence of pathogenicity PP3: Predicted by multiple statistical methods (REVEL), results show that the variant causes deleterious effects on the gene or gene product; Predicted by spliceAI with results showing that the variant may affect splicing; Evidence in favor of pathogenicity PM6_Supporting: a total of 1 patient with an atypical phenotype was reported in the literature where this variant was detected as de novo [PMID:23534934]; This known variant is rated as P in the ClinVar database; this known variant is rated in the HGMD database as DM [PMID:20650610;23534934;27484032;29312905;30443250]; Mutations in the gene FOXP3 (OMIM:300292) cause Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked (immune dysregulation, polyendocrinopathy, and enteropathy), as determined by a public database query (OMIM:304790). -

May 08, 2023

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 397 of the FOXP3 protein (p.Arg397Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with immunodysregulation, polyendocrinopathy, and enteropathy syndrome (PMID: 20650610, 23534934, 29312905). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 379222). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FOXP3 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg397 amino acid residue in FOXP3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11137992, 11295725, 25546394). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

FOXP3-related disorder Pathogenic:1

Dec 21, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FOXP3 c.1190G>A variant is predicted to result in the amino acid substitution p.Arg397Gln. This variant has been reported in individuals with IPEX syndrome, including at least one individual in whom it was reported to occur de novo (Tsuda et al. 2010. PubMed ID: 20650610; Martín-Santiago et al. 2013. PubMed ID: 23534934; Gambineri et al. 2018. PubMed ID: 30443250; El Hawary et al. 2022. PubMed ID: 35482138). Alternative nucleotide substitutions affecting the same amino acid (p.Arg397Trp, p.Arg397Leu) have also been described in individuals with IPEX syndrome (Xavier-da-Silva et al. 2015. PubMed ID: 25546394; Supplementary Table 1, Suspitsin et al. 2020. PubMed ID: 32441320). This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.70
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;.;D;.;.;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.;.;.;.;.
PhyloP100		5.0
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.7	D;D;.;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;.
Vest4		0.76
MutPred		0.78		Loss of MoRF binding (P = 0.0152);.;.;.;.;.;
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.95
gMVP		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.54		Position offset: -2

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

Other links and lift over

dbSNP: rs1057520529; hg19: chrX-49107901; COSMIC: COSV66051887; COSMIC: COSV66051887;