rs1557116163

Variant names:

• chrX-49255494-CCTT-C
• rs1557116163
• NM_014009.4:c.748_750delAAG

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_014009.4(FOXP3):​c.748_750delAAG​(p.Lys250del) variant causes a conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FOXP3 NM_014009.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 B:1
• Conservation: PhyloP100: 4.49

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

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a cross_link Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) (size 0) in uniprot entity FOXP3_HUMAN
• 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-49255494-CCTT-C is Pathogenic according to our data. Variant chrX-49255494-CCTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 499890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-49255494-CCTT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP3	NM_014009.4	c.748_750delAAG	p.Lys250del	conservative_inframe_deletion	Exon 8 of 12	ENST00000376207.10	NP_054728.2
FOXP3	NM_001114377.2	c.643_645delAAG	p.Lys215del	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.748_750delAAG	p.Lys250del	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/Likely pathogenic

Submissions summary: Pathogenic:3 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome Pathogenic:2 Benign:1

Aug 14, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.748_750del, results in the deletion of 1 amino acid(s) of the FOXP3 protein (p.Lys250del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect FOXP3 protein function (PMID: 16920951, 17586580). This variant has been observed in individual(s) with clinical features of immunodysregulation, polyendocrinopathy, and enteropathy (IPEX) syndrome (PMID: 29907148, 19189134, 12161590, 30443250, Invitae). This variant is also known as delE251. ClinVar contains an entry for this variant (Variation ID: 499890). -

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely benign

Review Status: flagged submission

Collection Method: research

Potent mutations in FOXP3 gene are associated with a rare X linked condition called IPEX. It presents with immune dysregulation, secretory diarrhea, polyendocrinopathy which includes diabtes type 1, thyroiditis, growth hormone deficiency and hypoadrenalism. It is associated with pancreatic beta cell destruction.However no sufficient evidence is found to ascertain the role of this particular variant rs1557116163, yet. -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The in-frame deletion p.K250del in FOXP3 (NM_014009.4) has been observed in multiple affected individuals with IPEX syndrome (Gambineri E et al,Wildin RS et al,Hashimura Y et al). The variant has been submitted to ClinVar as Pathogenic.The p.K250del variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant results in a deletion of a lysine at position 250 of the FOXP3 gene. However, as this is an in-frame deletion, it is not expected to result in either a truncated protein product or loss of protein through nonsense-mediated mRNA decay. The nucleotide c.748 in FOXP3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Mar 01, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=64/36	disease causing (ClinVar)

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: rs1557116163; hg19: chrX-49111955;