rs122467171

Variant names:

• chrX-49255491-TCTC-T
• rs122467171
• NM_014009.4:c.751_753delGAG

Variant summary

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

The NM_014009.4(FOXP3):​c.751_753delGAG​(p.Glu251del) variant causes a conservative 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 NM_014009.4 conservative_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 NM_014009.4. 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 rank	MANE	Protein	UniProt
FOXP3	NM_014009.4	c.751_753delGAG	p.Glu251del	conservative_inframe_deletion	Exon 8 of 12	ENST00000376207.10	NP_054728.2
FOXP3	NM_001114377.2	c.646_648delGAG	p.Glu216del	conservative_inframe_deletion	Exon 7 of 11		NP_001107849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP3	ENST00000376207.10	c.751_753delGAG	p.Glu251del	conservative_inframe_deletion	Exon 8 of 12	1	NM_014009.4	ENSP00000365380.4

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

Jun 16, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FOXP3: PS3, PM2, PS4:Moderate, PM4:Supporting, PP1, PP4 -

Insulin-dependent diabetes mellitus secretory diarrhea syndrome Pathogenic:2

Mar 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects FOXP3 function (PMID: 17586580). ClinVar contains an entry for this variant (Variation ID: 11413). 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. -

Dec 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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;