rs122467175

chrX-49251711-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_014009.4(FOXP3):c.1099T>C(p.Phe367Leu) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: FOXP3 NM_014009.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.21

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_014009.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant X-49251711-A-G is Pathogenic according to our data. Variant chrX-49251711-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 11419.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP3	NM_014009.4	c.1099T>C	p.Phe367Leu	missense_variant	11/12	ENST00000376207.10
FOXP3	NM_001114377.2	c.994T>C	p.Phe332Leu	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP3	ENST00000376207.10	c.1099T>C	p.Phe367Leu	missense_variant	11/12	1	NM_014009.4	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 26, 2020	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe367 amino acid residue in FOXP3. Other variant(s) that disrupt this residue have been observed in individuals with FOXP3-related conditions (PMID: 26748374, 18820676), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of X-linked recessive immunodysregulation, polyendocrinopathy, and enteropathy (IPEX syndrome) (PMID: 17635943, 22581967, 18795917, Invitae). ClinVar contains an entry for this variant (Variation ID: 11419). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 367 of the FOXP3 protein (p.Phe367Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;D;.;.;.
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.95	D;D;D;D;.;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.2	L;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.6	D;D;.;D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.017	D;D;.;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		0.49	P;B;P;D;B;.
Vest4		0.60
MutPred		0.86		Gain of MoRF binding (P = 0.109);.;.;.;.;.;
MVP		1.0
MPC		0.81
ClinPred		0.95	D
GERP RS		3.2
Varity_R		0.73
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs122467175; hg19: chrX-49108172;