X-49258394-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_014009.4(FOXP3):c.112G>T(p.Ala38Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000372 in 1,170,522 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 125 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.00041 ( 0 hom. 124 hem. )

Consequence

FOXP3
NM_014009.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.86

Publications

5 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.058613867).

BP6

Variant X-49258394-C-A is Benign according to our data. Variant chrX-49258394-C-A is described in ClinVar as Benign. ClinVar VariationId is 529765.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000407 (431/1057834) while in subpopulation NFE AF = 0.00052 (427/820952). AF 95% confidence interval is 0.000479. There are 0 homozygotes in GnomAdExome4. There are 124 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 124 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014009.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP3	NM_014009.4	MANE Select	c.112G>T	p.Ala38Ser	missense	Exon 2 of 12	NP_054728.2
	FOXP3	NM_001114377.2		c.112G>T	p.Ala38Ser	missense	Exon 2 of 11	NP_001107849.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FOXP3	ENST00000376207.10	TSL:1 MANE Select	c.112G>T	p.Ala38Ser	missense	Exon 2 of 12	ENSP00000365380.4
FOXP3	ENST00000518685.6	TSL:1	c.112G>T	p.Ala38Ser	missense	Exon 1 of 10	ENSP00000428952.2
ENSG00000290184	ENST00000703450.1		c.112G>T	p.Ala38Ser	missense	Exon 4 of 4	ENSP00000515301.1

Frequencies

GnomAD3 genomes

AF:

0.0000444

AC:

AN:

112688

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000506

AC:

AN:

118541

AF XY:

0.0000497

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000108

Gnomad OTH exome

AF:

0.000303

GnomAD4 exome

AF:

0.000407

AC:

431

AN:

1057834

Hom.:

Cov.:

AF XY:

0.000360

AC XY:

124

AN XY:

344716

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25391

American (AMR)

AF:

0.00

AC:

AN:

28529

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18670

East Asian (EAS)

AF:

0.00

AC:

AN:

27858

South Asian (SAS)

AF:

0.00

AC:

AN:

50161

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37702

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4069

European-Non Finnish (NFE)

AF:

0.000520

AC:

427

AN:

820952

Other (OTH)

AF:

0.0000899

AC:

AN:

44502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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

110

<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:

0.0000444

AC:

AN:

112688

Hom.:

Cov.:

AF XY:

0.0000287

AC XY:

AN XY:

34846

show subpopulations

African (AFR)

AF:

0.0000967

AC:

AN:

31018

American (AMR)

AF:

0.00

AC:

AN:

10766

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3565

South Asian (SAS)

AF:

0.00

AC:

AN:

2772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53238

Other (OTH)

AF:

0.00

AC:

AN:

1515

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:

0.00

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000378

AC:

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Insulin-dependent diabetes mellitus secretory diarrhea syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.063

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.26

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.84

M_CAP

Benign

0.064

MetaRNN

Benign

0.059

MetaSVM

Uncertain

-0.074

MutationAssessor

Benign

0.55

PhyloP100

-2.9

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.32

REVEL

Benign

0.20

Sift

Benign

0.17

Sift4G

Benign

0.31

Polyphen

0.044

Vest4

0.054

MVP

0.73

MPC

0.33

ClinPred

0.058

GERP RS

-8.9

PromoterAI

-0.068

Neutral

(source)

Varity_R

0.059

gMVP

0.070

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over