chrX-49257557-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_014009.4(FOXP3):c.324G>A(p.Thr108Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000405 in 1,186,433 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 102 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., 54 hem., cov: 23)

Exomes 𝑓: 0.00021 ( 0 hom. 48 hem. )

Consequence

FOXP3
NM_014009.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.48

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant X-49257557-C-T is Benign according to our data. Variant chrX-49257557-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 435252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.48 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00227 (254/112103) while in subpopulation AFR AF= 0.00783 (241/30783). AF 95% confidence interval is 0.00702. There are 0 homozygotes in gnomad4. There are 54 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 54 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP3	NM_014009.4 link	c.324G>A	p.Thr108Thr	synonymous_variant	Exon 4 of 12	ENST00000376207.10	NP_054728.2	Q9BZS1-1
FOXP3	NM_001114377.2 link	c.219G>A	p.Thr73Thr	synonymous_variant	Exon 3 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.324G>A	p.Thr108Thr	synonymous_variant	Exon 4 of 12	1	NM_014009.4	ENSP00000365380.4		Q9BZS1-1

Frequencies

GnomAD3 genomes

AF:

0.00221

AC:

248

AN:

112051

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

AN XY:

34243

show subpopulations

Gnomad AFR

AF:

0.00765

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000751

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:

0.0000565

Gnomad OTH

AF:

0.00133

GnomAD3 exomes

AF:

0.000646

AC:

103

AN:

159455

Hom.:

AF XY:

0.000382

AC XY:

AN XY:

49717

show subpopulations

Gnomad AFR exome

AF:

0.00762

Gnomad AMR exome

AF:

0.000195

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000686

Gnomad FIN exome

AF:

0.0000741

Gnomad NFE exome

AF:

0.0000285

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000210

AC:

226

AN:

1074330

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

AN XY:

346556

show subpopulations

Gnomad4 AFR exome

AF:

0.00695

Gnomad4 AMR exome

AF:

0.000235

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000336

Gnomad4 SAS exome

AF:

0.0000391

Gnomad4 FIN exome

AF:

0.0000504

Gnomad4 NFE exome

AF:

0.00000605

Gnomad4 OTH exome

AF:

0.000600

GnomAD4 genome

AF:

0.00227

AC:

254

AN:

112103

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

AN XY:

34305

show subpopulations

Gnomad4 AFR

AF:

0.00783

Gnomad4 AMR

AF:

0.000750

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000565

Gnomad4 OTH

AF:

0.00131

Alfa

AF:

0.00135

Hom.:

Bravo

AF:

0.00241

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jul 19, 2018

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 23, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Insulin-dependent diabetes mellitus secretory diarrhea syndrome

Benign:2

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

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 rs111856931, yet. -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FOXP3-related disorder

Benign:1

Oct 29, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

3.6

DANN

Benign

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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