X-49251359-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_014009.4(FOXP3):c.1271G>A(p.Cys424Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. C424?) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: FOXP3 NM_014009.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0570

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-49251359-C-T is Pathogenic according to our data. Variant chrX-49251359-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2584421.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP3	NM_014009.4	c.1271G>A	p.Cys424Tyr	missense_variant	12/12	ENST00000376207.10
FOXP3	NM_001114377.2	c.1166G>A	p.Cys389Tyr	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP3	ENST00000376207.10	c.1271G>A	p.Cys424Tyr	missense_variant	12/12	1	NM_014009.4	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This variant has been previously reported as a hemizygous change in patients with Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-Linked (IPEX) Syndrome (PMID: 16990602, 30443250). In vitro studies demonstrate that this variant impairs the transcriptional repressor activity of FOXP3 (PMID: 1692095). It is absent from the gnomAD population database and thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. Analysis of the maternal sample was negative for the variant, indicating the variant likely occurred as a de novo event. Based on the available evidence, the c.1271G>A (p.Cys424Tyr) variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.;T;.;.;.
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.79	T;T;T;T;.;T
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.22	T;T;T;T;T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	-1.0	N;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;N;.;N;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;D;.;D;D;D
Sift4G	Uncertain	0.014	D;D;T;D;D;D
Polyphen		0.0	B;B;B;B;B;.
Vest4		0.12
MutPred		0.14		Gain of phosphorylation at C424 (P = 0.0241);.;.;.;.;.;
MVP		0.99
MPC		0.63
ClinPred		0.21	T
GERP RS		3.6
Varity_R		0.46
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.57		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-49107820;