X-49251377-C-T

Variant summary

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

The NM_014009.4(FOXP3):c.1253G>A(p.Ser418Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,431 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. S418G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: FOXP3 NM_014009.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63

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 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=0.35456532).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP3	NM_014009.4	c.1253G>A	p.Ser418Asn	missense_variant	12/12	ENST00000376207.10
FOXP3	NM_001114377.2	c.1148G>A	p.Ser383Asn	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP3	ENST00000376207.10	c.1253G>A	p.Ser418Asn	missense_variant	12/12	1	NM_014009.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097431 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362849

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

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

May 03, 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 serine with asparagine at codon 418 of the FOXP3 protein (p.Ser418Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.;T;.;.;.
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.85	D;D;D;T;.;T
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.35	T;T;T;T;T;T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	0.84	L;.;.;.;.;.
MutationTaster	Benign	0.74	D;D;D;D;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.3	N;N;.;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.042	D;T;.;D;T;D
Sift4G	Benign	0.079	T;T;D;T;T;D
Polyphen		1.0	D;D;D;P;D;.
Vest4		0.26
MutPred		0.28		Loss of phosphorylation at S418 (P = 0.0065);.;.;.;.;.;
MVP		0.91
MPC		0.38
ClinPred		0.89	D
GERP RS		4.6
Varity_R		0.35
gMVP		0.74

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-49107838;