rs2232367

Positions:

chrX-49256855-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id is 129111.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=5}. Variant chrX-49256855-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 54 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXP3	NM_014009.4 linkuse as main transcript	c.543C>T	p.Ser181Ser	splice_region_variant, synonymous_variant	6/12	ENST00000376207.10	NP_054728.2	Q9BZS1-1
FOXP3	NM_001114377.2 linkuse as main transcript	c.438C>T	p.Ser146Ser	splice_region_variant, synonymous_variant	5/11		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.543C>T	p.Ser181Ser	splice_region_variant, synonymous_variant	6/12	1	NM_014009.4	ENSP00000365380.4		Q9BZS1-1

Frequencies

GnomAD3 genomes

AF:

0.0294

AC:

3314

AN:

112634

Hom.:

Cov.:

AF XY:

0.0291

AC XY:

1012

AN XY:

34790

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

GnomAD3 exomes

AF:

0.0315

AC:

5768

AN:

183213

Hom.:

100

AF XY:

0.0315

AC XY:

2132

AN XY:

67689

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 SAS exome

AF:

0.0171

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

Gnomad4 AFR exome

AF:

0.00409

Gnomad4 AMR exome

AF:

0.0151

Gnomad4 ASJ exome

AF:

0.0751

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.0165

Gnomad4 FIN exome

AF:

0.0522

Gnomad4 NFE exome

AF:

0.0370

Gnomad4 OTH exome

AF:

0.0331

GnomAD4 genome

AF:

0.0294

AC:

3314

AN:

112685

Hom.:

Cov.:

AF XY:

0.0290

AC XY:

1012

AN XY:

34851

show subpopulations

Gnomad4 AFR

AF:

0.00559

Gnomad4 AMR

AF:

0.0300

Gnomad4 ASJ

AF:

0.0826

Gnomad4 EAS

AF:

0.000281

Gnomad4 SAS

AF:

0.00832

Gnomad4 FIN

AF:

0.0540

Gnomad4 NFE

AF:

0.0408

Gnomad4 OTH

AF:

0.0313

Alfa

AF:

0.0405

Hom.:

1500

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

Uncertain significance, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 17, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 27, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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% -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 20, 2016	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2019	This variant is associated with the following publications: (PMID: 22132891, 12819471, 23374272, 16741580, 12161590, 11753102, 27884173, 29241729) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 09, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.64

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

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