rs200554980

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_014009.4(FOXP3):c.340C>T(p.Arg114Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000168 in 1,179,256 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 62 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R114Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., 11 hem., cov: 23)

Exomes 𝑓: 0.00016 ( 0 hom. 51 hem. )

Consequence

FOXP3
NM_014009.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.54

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07122582).

BP6

Variant X-49257541-G-A is Benign according to our data. Variant chrX-49257541-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435256.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAd at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP3	NM_014009.4 linkuse as main transcript	c.340C>T	p.Arg114Trp	missense_variant	4/12	ENST00000376207.10
FOXP3	NM_001114377.2 linkuse as main transcript	c.235C>T	p.Arg79Trp	missense_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP3	ENST00000376207.10 linkuse as main transcript	c.340C>T	p.Arg114Trp	missense_variant	4/12	1	NM_014009.4	P1	Q9BZS1-1

Frequencies

GnomAD3 genomes

AF:

0.000214

AC:

AN:

111987

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

34187

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000939

Gnomad ASJ

AF:

0.00795

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000264

AC:

AN:

155102

Hom.:

AF XY:

0.000309

AC XY:

AN XY:

48538

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000788

Gnomad ASJ exome

AF:

0.00595

Gnomad EAS exome

AF:

0.0000746

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000731

Gnomad OTH exome

AF:

0.000522

GnomAD4 exome

AF:

0.000163

AC:

174

AN:

1067269

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

343677

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000592

Gnomad4 ASJ exome

AF:

0.00636

Gnomad4 EAS exome

AF:

0.0000336

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000486

Gnomad4 OTH exome

AF:

0.000425

GnomAD4 genome

AF:

0.000214

AC:

AN:

111987

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

34187

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000939

Gnomad4 ASJ

AF:

0.00795

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000340

Hom.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000141

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 03, 2016

- -

Insulin-dependent diabetes mellitus secretory diarrhea syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.16

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.38

T;.;T;.;.;.

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.95

D;D;D;D;.;D

M_CAP

Pathogenic

0.84

MetaRNN

Benign

0.071

T;T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.90

L;.;.;.;.;.

MutationTaster

Benign

0.62

D;D;N;N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.4

N;N;N;N;N;N

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D;D;T

Polyphen

1.0

D;D;D;D;D;.

Vest4

0.51

MVP

0.95

MPC

1.0

ClinPred

0.082

GERP RS

5.3

Varity_R

0.26

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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