rs782511378

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5BP4

The NM_014009.4(FOXP3):c.398C>T(p.Pro133Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000261 in 1,148,644 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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 0.0000089 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.0000019 ( 0 hom. 1 hem. )

Consequence

FOXP3
NM_014009.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.94

Publications

3 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: Uncertain_significance. The variant received 0 ACMG points.

PP5

Variant X-49257483-G-A is Pathogenic according to our data. Variant chrX-49257483-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 268095.

BP4

Computational evidence support a benign effect (MetaRNN=0.32187414). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP3	NM_014009.4 link	c.398C>T	p.Pro133Leu	missense_variant	Exon 4 of 12	ENST00000376207.10	NP_054728.2	Q9BZS1-1
FOXP3	NM_001114377.2 link	c.293C>T	p.Pro98Leu	missense_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.398C>T	p.Pro133Leu	missense_variant	Exon 4 of 12	1	NM_014009.4	ENSP00000365380.4		Q9BZS1-1

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111814

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000282

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

GnomAD2 exomes

AF:

0.0000224

AC:

AN:

133709

AF XY:

0.0000470

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000239

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000193

AC:

AN:

1036830

Hom.:

Cov.:

AF XY:

0.00000302

AC XY:

AN XY:

330986

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24718

American (AMR)

AF:

0.00

AC:

AN:

27336

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15324

East Asian (EAS)

AF:

0.0000676

AC:

AN:

29567

South Asian (SAS)

AF:

0.00

AC:

AN:

44957

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38028

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3625

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

809945

Other (OTH)

AF:

0.00

AC:

AN:

43330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000894

AC:

AN:

111814

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

33990

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30677

American (AMR)

AF:

0.00

AC:

AN:

10612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.000282

AC:

AN:

3549

South Asian (SAS)

AF:

0.00

AC:

AN:

2702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6092

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53117

Other (OTH)

AF:

0.00

AC:

AN:

1499

Age Distribution

Genome Hom

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000425

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Diabetes mellitus type 1

Pathogenic:1

Aug 15, 2016

Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Aug 15, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FOXP3 c.398C>T (p.Pro133Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 133709 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.398C>T in individuals affected with Insulin-Dependent Diabetes Mellitus Secretory Diarrhea Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 268095). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;.;T;.;.;.

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.92

D;D;D;D;.;D

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.32

T;T;T;T;T;T

MetaSVM

Pathogenic

0.95

MutationAssessor

Benign

0.97

L;.;.;.;.;.

PhyloP100

2.9

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.8

N;N;N;D;N;N

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Uncertain

0.019

D;T;D;D;T;D

Polyphen

1.0

D;D;D;D;D;.

Vest4

0.26

MutPred

0.42

Loss of sheet (P = 0.0084);.;Loss of sheet (P = 0.0084);.;.;.;

MVP

0.92

MPC

0.72

ClinPred

0.75

GERP RS

5.1

Varity_R

0.24

gMVP

0.53

Mutation Taster

=84/16

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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