rs367860281

Positions:

chrX-49253186-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_014009.4(FOXP3):c.984G>A(p.Met328Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,207,149 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000029 ( 0 hom. 16 hem. )

Consequence

FOXP3
NM_014009.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.0810

Variant links:

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]

FOXP3 links:

FOXP3 (HGNC:):

FOXP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6

Variant X-49253186-C-T is Benign according to our data. Variant chrX-49253186-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 460309.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

BS2

High Hemizygotes in GnomAdExome4 at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXP3	NM_014009.4 linkuse as main transcript	c.984G>A	p.Met328Ile	missense_variant	10/12	ENST00000376207.10	NP_054728.2	Q9BZS1-1
FOXP3	NM_001114377.2 linkuse as main transcript	c.879G>A	p.Met293Ile	missense_variant	9/11		NP_001107849.1	Q9BZS1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXP3	ENST00000376207.10 linkuse as main transcript	c.984G>A	p.Met328Ile	missense_variant	10/12	1	NM_014009.4	ENSP00000365380.4		Q9BZS1-1

Frequencies

GnomAD3 genomes

AF:

0.0000631

AC:

AN:

110862

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

33104

show subpopulations

Gnomad AFR

AF:

0.000198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000955

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000447

AC:

AN:

178800

Hom.:

AF XY:

0.0000313

AC XY:

AN XY:

63800

show subpopulations

Gnomad AFR exome

AF:

0.000233

Gnomad AMR exome

AF:

0.000147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000126

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000292

AC:

AN:

1096287

Hom.:

Cov.:

AF XY:

0.0000442

AC XY:

AN XY:

361793

show subpopulations

Gnomad4 AFR exome

AF:

0.000265

Gnomad4 AMR exome

AF:

0.000114

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:

0.0000226

Gnomad4 OTH exome

AF:

0.0000435

GnomAD4 genome

AF:

0.0000631

AC:

AN:

110862

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

33104

show subpopulations

Gnomad4 AFR

AF:

0.000198

Gnomad4 AMR

AF:

0.0000955

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000117

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 14, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 17, 2020

DNA sequence analysis of the FOXP3 gene demonstrated a sequence change, c.984G>A, in exon 10 that results in an amino acid change, p.Met328Ile. This sequence change does not appear to have been previously described in patients with FOXP3-related disorders. It has been described in the gnomAD database with a low population frequency of 0.005% (dbSNP rs367860281). The p.Met328Ile change affects a highly conserved amino acid residue of the FOXP3 protein. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Met328Ile substitution. Due to these contrasting evidences and the lack of functional study, the clinical significance of the p.Met328Ile change remains unknown at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Benign

0.95

DEOGEN2

Benign

0.40

T;.;T;.;.;.

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.89

D;D;D;D;.;D

M_CAP

Pathogenic

0.78

MetaRNN

Benign

0.21

T;T;T;T;T;T

MetaSVM

Uncertain

0.79

MutationAssessor

Benign

1.7

L;.;.;.;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.4

N;N;.;N;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.38

T;T;.;T;T;T

Sift4G

Benign

0.39

T;T;T;T;T;T

Polyphen

0.062

B;B;B;B;B;.

Vest4

0.27

MutPred

0.50

Loss of catalytic residue at M328 (P = 0.0055);.;.;.;.;.;

MVP

0.91

MPC

0.46

ClinPred

0.041

GERP RS

5.1

Varity_R

0.36

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.83

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.83

Position offset: -2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over