NM_014009.4:c.176C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014009.4(FOXP3):c.176C>G(p.Ser59Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000256 in 1,165,735 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 81 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 0.0014 ( 0 hom., 47 hem., cov: 24)

Exomes 𝑓: 0.00014 ( 0 hom. 34 hem. )

Consequence

FOXP3
NM_014009.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:4

Conservation

PhyloP100: 4.46

Publications

1 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:

ENSG00000290184 (HGNC:):

ENSG00000290184 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009704351).

BP6

Variant X-49258330-G-C is Benign according to our data. Variant chrX-49258330-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 549556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00138 (155/112596) while in subpopulation AFR AF = 0.00467 (145/31023). AF 95% confidence interval is 0.00405. There are 0 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 47 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP3	NM_014009.4 link	c.176C>G	p.Ser59Cys	missense_variant	Exon 2 of 12	ENST00000376207.10	NP_054728.2
FOXP3	NM_001114377.2 link	c.176C>G	p.Ser59Cys	missense_variant	Exon 2 of 11		NP_001107849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP3	ENST00000376207.10 link	c.176C>G	p.Ser59Cys	missense_variant	Exon 2 of 12	1	NM_014009.4	ENSP00000365380.4
ENSG00000290184	ENST00000703450.1 link	c.*13C>G		downstream_gene_variant				ENSP00000515301.1

Frequencies

GnomAD3 genomes

AF:

0.00138

AC:

155

AN:

112542

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00468

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000465

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:

0.0000564

Gnomad OTH

AF:

0.00132

GnomAD2 exomes

AF:

0.000434

AC:

AN:

112943

AF XY:

0.000226

show subpopulations

Gnomad AFR exome

AF:

0.00621

Gnomad AMR exome

AF:

0.000206

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000234

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000137

AC:

144

AN:

1053139

Hom.:

Cov.:

AF XY:

0.0000988

AC XY:

AN XY:

344035

show subpopulations

African (AFR)

AF:

0.00446

AC:

111

AN:

24914

American (AMR)

AF:

0.000287

AC:

AN:

27889

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18610

East Asian (EAS)

AF:

0.00

AC:

AN:

27139

South Asian (SAS)

AF:

0.00

AC:

AN:

49816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4068

European-Non Finnish (NFE)

AF:

0.00000733

AC:

AN:

818850

Other (OTH)

AF:

0.000428

AC:

AN:

44349

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00138

AC:

155

AN:

112596

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

AN XY:

34764

show subpopulations

African (AFR)

AF:

0.00467

AC:

145

AN:

31023

American (AMR)

AF:

0.000464

AC:

AN:

10765

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3551

South Asian (SAS)

AF:

0.00

AC:

AN:

2733

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6239

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000564

AC:

AN:

53199

Other (OTH)

AF:

0.00131

AC:

AN:

1531

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000641

Hom.:

Bravo

AF:

0.00149

ESP6500AA

AF:

0.00483

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000302

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome

Pathogenic:1Benign:3

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Likely risk allele

Review Status:flagged submission

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 rs199917616, yet. -

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.4% (145/30954) including 45 hemizygotes (https://gnomad.broadinstitute.org/variant/X-49258330-G-C?dataset=gnomad_r3). This variant is present in ClinVar, with multiple labs classifying this variant as Benign (Variation ID:549556). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

Dec 19, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Monogenic diabetes

Benign:1

May 18, 2018

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

ACMG criteria: [PP3 (7 predictors), BP4 (4 predictors), Revel score 0.527 so not using data], BS2 (8 hemizogotes in gnomAD African), BS1 (0.4 MAF in gnomAD Africans, IPEX is estimated to affect fewer than 1 in 1 million per GHR & Orphanet)= benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;.;T;.;.;.

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.81

T;T;T;T;.;T

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.0097

T;T;T;T;T;T

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

0.97

L;L;.;L;L;.

PhyloP100

4.5

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.88

N;N;N;N;N;N

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Uncertain

0.036

D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;D;.

Vest4

0.34

MVP

0.91

MPC

1.1

ClinPred

0.030

GERP RS

4.3

PromoterAI

-0.029

Neutral

(source)

Varity_R

0.19

gMVP

0.34

Mutation Taster

=98/2

polymorphism

(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