X-49251378-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_014009.4(FOXP3):c.1252A>G(p.Ser418Gly) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S418N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: FOXP3 NM_014009.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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 2 ACMG points.

• PM1: In a mutagenesis_site Slight increase in transcriptional repressor activity. (size 0) in uniprot entity FOXP3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24131078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP3	NM_014009.4	c.1252A>G	p.Ser418Gly	missense_variant	12/12	ENST00000376207.10
FOXP3	NM_001114377.2	c.1147A>G	p.Ser383Gly	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP3	ENST00000376207.10	c.1252A>G	p.Ser418Gly	missense_variant	12/12	1	NM_014009.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 27, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 418 of the FOXP3 protein (p.Ser418Gly). This variant has not been reported in the literature in individuals affected with FOXP3-related conditions. 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.;T;.;.;.
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.79	T;T;T;T;.;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.24	T;T;T;T;T;T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	0.41	N;.;.;.;.;.
MutationTaster	Benign	0.75	D;D;D;D;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.70	N;N;.;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.50	T;T;.;T;T;T
Sift4G	Benign	0.86	T;T;T;T;T;T
Polyphen		1.0	D;D;D;B;D;.
Vest4		0.25
MutPred		0.34		Loss of phosphorylation at S418 (P = 0.0065);.;.;.;.;.;
MVP		0.97
MPC		0.70
ClinPred		0.84	D
GERP RS		4.6
Varity_R		0.12
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-49107839;