rs1557115532
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_014009.4(FOXP3):c.1222G>A(p.Val408Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 22)
Consequence
FOXP3
NM_014009.4 missense
NM_014009.4 missense
Scores
10
6
1
Clinical Significance
Conservation
PhyloP100: 6.11
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
?
In a DNA_binding_region Fork-head (size 86) in uniprot entity FOXP3_HUMAN there are 22 pathogenic changes around while only 3 benign (88%) in NM_014009.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.89
PP5
?
Variant X-49251408-C-T is Pathogenic according to our data. Variant chrX-49251408-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 435255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FOXP3 | NM_014009.4 | c.1222G>A | p.Val408Met | missense_variant | 12/12 | ENST00000376207.10 | |
FOXP3 | NM_001114377.2 | c.1117G>A | p.Val373Met | missense_variant | 11/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FOXP3 | ENST00000376207.10 | c.1222G>A | p.Val408Met | missense_variant | 12/12 | 1 | NM_014009.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Insulin-dependent diabetes mellitus secretory diarrhea syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 408 of the FOXP3 protein (p.Val408Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of IPEX syndrome, congenital enteropathy, and/or neonatal diabetes (PMID: 18931102, 30443250, 30894704, 32279225, 33833438, 34216291). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 435255). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 02, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 29, 2022 | Variant summary: FOXP3 c.1222G>A (p.Val408Met) results in a conservative amino acid change located in the Fork head domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182058 control chromosomes. c.1222G>A has been reported in the literature in individuals affected with Insulin-Dependent Diabetes Mellitus Secretory Diarrhea Syndrome. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
FOXP3-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 28, 2022 | The FOXP3 c.1222G>A variant is predicted to result in the amino acid substitution p.Val408Met. This variant was reported in individuals with neonatal diabetes and/or IPEX syndrome (Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked) (Rubio-Cabezas et al. 2009. PubMed ID: 18931102; Gambineri et al. 2018. PubMed ID: 30443250; Supplementary Table 1, Ye et al. 2019. PubMed ID: 30894704; Cao et al. 2020. PubMed ID: 32279225; Zemmour et al. 2021. PubMed ID: 33833438). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;D;.;.;.
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
D;D;D;D;D;.
Vest4
MutPred
Loss of sheet (P = 0.0817);.;.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at