X-49251373-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_014009.4(FOXP3):c.1257G>C(p.Gln419His) 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 (★). Synonymous variant affecting the same amino acid position (i.e. Q419Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: FOXP3 NM_014009.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.276

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 3 ACMG points.

• PM1: In a DNA_binding_region Fork-head (size 86) in uniprot entity FOXP3_HUMAN there are 22 pathogenic changes around while only 3 benign (88%) in NM_014009.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36666077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP3	NM_014009.4	c.1257G>C	p.Gln419His	missense_variant	12/12	ENST00000376207.10
FOXP3	NM_001114377.2	c.1152G>C	p.Gln384His	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP3	ENST00000376207.10	c.1257G>C	p.Gln419His	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

Jan 28, 2021

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 expected to disrupt FOXP3 protein function. This variant has not been reported in the literature in individuals with FOXP3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with histidine at codon 419 of the FOXP3 protein (p.Gln419His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;T;.;.;.
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.87	D;D;D;D;.;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.37	T;T;T;T;T;T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.3	M;.;.;.;.;.
MutationTaster	Benign	0.93	D;D;D;D;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	D;D;.;D;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0040	D;D;.;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;.
Vest4		0.24
MutPred		0.42		Loss of methylation at K416 (P = 0.0865);.;.;.;.;.;
MVP		0.97
MPC		1.1
ClinPred		0.98	D
GERP RS		-0.88
Varity_R		0.24
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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-49107834;