X-49253200-A-G

Position:

• chrX-49253200-A-G

Variant summary

Our verdict is Likely benign. Variant got -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

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_benign. Variant got -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 id is 11416.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• 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/exons	MANE	UniProt
FOXP3	NM_014009.4	c.970T>C	p.Phe324Leu	missense_variant, splice_region_variant	10/12	ENST00000376207.10
FOXP3	NM_001114377.2	c.865T>C	p.Phe289Leu	missense_variant, splice_region_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP3	ENST00000376207.10	c.970T>C	p.Phe324Leu	missense_variant, splice_region_variant	10/12	1	NM_014009.4	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

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

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 15, 2023	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2006	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 24, 2024	- -

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;.;.;.
FATHMM_MKL	Benign	0.25	N
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;.;.;.;.;.
MutationTaster	Benign	0.27	A;A;A;A;A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.44	N;N;D;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.61	T;T;D;T;T;T
Sift4G	Benign	0.75	T;T;T;T;T;T
Polyphen		0.0050	B;B;B;B;B;.
Vest4		0.12
MutPred		0.30		Gain of disorder (P = 0.1536);.;.;.;.;.;
MVP		1.0
MPC		0.48
ClinPred		0.11	T
GERP RS		3.9
Varity_R		0.12
gMVP		0.89

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: rs122467173; hg19: chrX-49109661;