X-49253200-A-G

Variant names:

• chrX-49253200-A-G
• rs122467173
• NM_014009.4:c.970T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP5 BP4 BS2

The NM_014009.4(FOXP3):​c.970T>C​(p.Phe324Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,093,705 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F324V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
• Consequence: FOXP3 NM_014009.4 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 0.298
• Publications: 10 publications found

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]

FOXP3 Gene-Disease associations (from GenCC):

• immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PP5: Variant X-49253200-A-G is Pathogenic according to our data. Variant chrX-49253200-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11416.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36225215). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP3	NM_014009.4	c.970T>C	p.Phe324Leu	missense_variant, splice_region_variant	Exon 10 of 12	ENST00000376207.10	NP_054728.2
FOXP3	NM_001114377.2	c.865T>C	p.Phe289Leu	missense_variant, splice_region_variant	Exon 9 of 11		NP_001107849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP3	ENST00000376207.10	c.970T>C	p.Phe324Leu	missense_variant, splice_region_variant	Exon 10 of 12	1	NM_014009.4	ENSP00000365380.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1093705 Hom.: 0 Cov.: 29 AF XY: 0.00000557 AC XY: 2 AN XY: 359315

African (AFR) AF: 0.00 AC: 0 AN: 26317

American (AMR) AF: 0.00 AC: 0 AN: 35045

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19318

East Asian (EAS) AF: 0.00 AC: 0 AN: 30108

South Asian (SAS) AF: 0.00 AC: 0 AN: 53461

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 839043

Other (OTH) AF: 0.00 AC: 0 AN: 45924

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jan 24, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Nov 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 324 of the FOXP3 protein (p.Phe324Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of IPEX syndrome (PMID: 16741580, 21036387; Invitae). ClinVar contains an entry for this variant (Variation ID: 11416). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FOXP3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect FOXP3 function (PMID: 16741580, 21036387). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.25	T;.;T;.;.;.
LIST_S2	Uncertain	0.87	D;D;D;D;.;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.36	T;T;T;T;T;T
MetaSVM	Uncertain	0.027	D
MutationAssessor	Benign	1.8	L;.;.;.;.;.
PhyloP100		0.30
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.44	N;N;D;N;N;N
Sift	Benign	0.61	T;T;D;T;T;T
Sift4G	Benign	0.75	T;T;T;T;T;T
Vest4		0.12
ClinPred		0.11	T
GERP RS		3.9
Varity_R		0.12
gMVP		0.89
Mutation Taster		=92/8	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs122467173; hg19: chrX-49109661;