rs122467175

Variant names:

• chrX-49251711-A-G
• rs122467175
• NM_014009.4:c.1099T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. 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 6 ACMG points.

• 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 rank	MANE	Protein	UniProt
FOXP3	NM_014009.4	c.1099T>C	p.Phe367Leu	missense_variant	Exon 11 of 12	ENST00000376207.10	NP_054728.2
FOXP3	NM_001114377.2	c.994T>C	p.Phe332Leu	missense_variant	Exon 10 of 11		NP_001107849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP3	ENST00000376207.10	c.1099T>C	p.Phe367Leu	missense_variant	Exon 11 of 12	1	NM_014009.4	ENSP00000365380.4

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

Oct 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 26, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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). 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 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. For these reasons, this variant has been classified as Pathogenic. -

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;.;.;.;.;.
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;