rs122467171

Positions:

• chrX-49255491-TCTC-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The ENST00000376207.10(FOXP3):​c.751_753del​(p.Glu251del) variant causes a inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FOXP3 ENST00000376207.10 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.14

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000376207.10. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant X-49255491-TCTC-T is Pathogenic according to our data. Variant chrX-49255491-TCTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 11413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXP3	NM_014009.4	c.751_753del	p.Glu251del	inframe_deletion	8/12	ENST00000376207.10	NP_054728.2
FOXP3	NM_001114377.2	c.646_648del	p.Glu216del	inframe_deletion	7/11		NP_001107849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXP3	ENST00000376207.10	c.751_753del	p.Glu251del	inframe_deletion	8/12	1	NM_014009.4	ENSP00000365380	P1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2023	In-frame deletion of 1 amino acids in a non-repeat region predicted to critically alter the protein; Published functional studies demonstrate a damaging effect with this variant disrupting homodimerization resulting in a failure to associate with the IL-2 promoter and reduced IL-2 transcription repression (Li et al., 2007); In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21458306, 33194927, 34786169, 11120765, 33614561, 31386175, 24916357, 30443250, 32531870, 20537998, 17586580) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	FOXP3: PS3, PM2, PS4:Moderate, PM4:Supporting, PP1, PP4 -

Insulin-dependent diabetes mellitus secretory diarrhea syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 26, 2022	ClinVar contains an entry for this variant (Variation ID: 11413). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects FOXP3 function (PMID: 17586580). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant has been observed in individuals with clinical features of X-linked recessive immunodysregulation, polyendocrinopathy, and enteropathy (IPEX syndrome) (PMID: 11120765, 20537998, 24916357, 30443250, 32531870). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.751_753del, results in the deletion of 1 amino acid(s) of the FOXP3 protein (p.Glu251del), but otherwise preserves the integrity of the reading frame. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2000	- -

Computational scores

Source: dbNSFP v4.3

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: rs122467171; hg19: chrX-49111952;