rs1557115532

Positions:

• chrX-49251408-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.69
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;D;.;.;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D;D;D;.;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	D;D;.;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;.;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		0.99	D;D;D;D;D;.
Vest4		0.61
MutPred		0.46		Loss of sheet (P = 0.0817);.;.;.;.;.;
MVP		1.0
MPC		1.1
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.80
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs1557115532; hg19: chrX-49107869;