rs2232367

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014009.4(FOXP3):c.543C>T(p.Ser181Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0341 in 1,209,803 control chromosomes in the GnomAD database, including 594 homozygotes. There are 13,451 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.029 ( 54 hom., 1012 hem., cov: 23)

Exomes 𝑓: 0.035 ( 540 hom. 12439 hem. )

Consequence

FOXP3
NM_014009.4 splice_region, synonymous

Scores

Splicing: ADA: 0.03634

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 0.652

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

FOXP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant X-49256855-G-A is Benign according to our data. Variant chrX-49256855-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129111.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0294 (3314/112685) while in subpopulation NFE AF = 0.0408 (2169/53212). AF 95% confidence interval is 0.0393. There are 54 homozygotes in GnomAd4. There are 1012 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 54 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP3	NM_014009.4 link	c.543C>T	p.Ser181Ser	splice_region_variant, synonymous_variant	Exon 6 of 12	ENST00000376207.10	NP_054728.2	Q9BZS1-1
FOXP3	NM_001114377.2 link	c.438C>T	p.Ser146Ser	splice_region_variant, synonymous_variant	Exon 5 of 11		NP_001107849.1	Q9BZS1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP3	ENST00000376207.10 link	c.543C>T	p.Ser181Ser	splice_region_variant, synonymous_variant	Exon 6 of 12	1	NM_014009.4	ENSP00000365380.4		Q9BZS1-1

Frequencies

GnomAD3 genomes

AF:

0.0294

AC:

3314

AN:

112634

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00560

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.0300

Gnomad ASJ

AF:

0.0826

Gnomad EAS

AF:

0.000280

Gnomad SAS

AF:

0.00794

Gnomad FIN

AF:

0.0540

Gnomad MID

AF:

0.0460

Gnomad NFE

AF:

0.0408

Gnomad OTH

AF:

0.0324

GnomAD2 exomes

AF:

0.0315

AC:

5768

AN:

183213

AF XY:

0.0315

show subpopulations

Gnomad AFR exome

AF:

0.00510

Gnomad AMR exome

AF:

0.0141

Gnomad ASJ exome

AF:

0.0757

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0502

Gnomad NFE exome

AF:

0.0425

Gnomad OTH exome

AF:

0.0327

GnomAD4 exome

AF:

0.0346

AC:

37948

AN:

1097118

Hom.:

540

Cov.:

AF XY:

0.0343

AC XY:

12439

AN XY:

362552

show subpopulations

African (AFR)

AF:

0.00409

AC:

108

AN:

26386

American (AMR)

AF:

0.0151

AC:

530

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.0751

AC:

1456

AN:

19379

East Asian (EAS)

AF:

0.0000662

AC:

AN:

30202

South Asian (SAS)

AF:

0.0165

AC:

891

AN:

54113

European-Finnish (FIN)

AF:

0.0522

AC:

2113

AN:

40492

Middle Eastern (MID)

AF:

0.0486

AC:

201

AN:

4132

European-Non Finnish (NFE)

AF:

0.0370

AC:

31122

AN:

841150

Other (OTH)

AF:

0.0331

AC:

1525

AN:

46063

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1335

2669

4004

5338

6673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1106

2212

3318

4424

5530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0294

AC:

3314

AN:

112685

Hom.:

Cov.:

AF XY:

0.0290

AC XY:

1012

AN XY:

34851

show subpopulations

African (AFR)

AF:

0.00559

AC:

174

AN:

31125

American (AMR)

AF:

0.0300

AC:

322

AN:

10746

Ashkenazi Jewish (ASJ)

AF:

0.0826

AC:

219

AN:

2651

East Asian (EAS)

AF:

0.000281

AC:

AN:

3555

South Asian (SAS)

AF:

0.00832

AC:

AN:

2763

European-Finnish (FIN)

AF:

0.0540

AC:

335

AN:

6202

Middle Eastern (MID)

AF:

0.0505

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0408

AC:

2169

AN:

53212

Other (OTH)

AF:

0.0313

AC:

AN:

1533

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

116

232

348

464

580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0377

Hom.:

1554

Bravo

AF:

0.0279

EpiCase

AF:

0.0456

EpiControl

AF:

0.0419

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome

Uncertain:1Benign:2

Nov 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Potent mutations in FOXP3 gene are associated with a rare X linked condition called IPEX. It presents with immune dysregulation, secretory diarrhea, polyendocrinopathy which includes diabtes type 1, thyroiditis, growth hormone deficiency and hypoadrenalism. It is associated with pancreatic beta cell destruction. However no sufficient evidence is found to ascertain the role of this particular variant rs2232367, yet. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Mar 27, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 20, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all):314/10563= 2.97% -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 23, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22132891, 12819471, 23374272, 16741580, 12161590, 11753102, 27884173, 29241729) -

Mar 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.64

PhyloP100

0.65

Mutation Taster

=84/16

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.036

dbscSNV1_RF

Benign

0.64

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over