Genetic Variant FOXP3:p.Ala145Val (chrX-49257447-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_014009.4(FOXP3):c.434C>T(p.Ala145Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

FOXP3
NM_014009.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.54

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant X-49257447-G-A is Pathogenic according to our data. Variant chrX-49257447-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 211045.Status of the report is criteria_provided_single_submitter, 1 stars.

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.434C>T	p.Ala145Val	missense	Exon 4 of 12	NP_054728.2
	FOXP3	NM_001114377.2		c.329C>T	p.Ala110Val	missense	Exon 3 of 11	NP_001107849.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FOXP3	ENST00000376207.10	TSL:1 MANE Select	c.434C>T	p.Ala145Val	missense	Exon 4 of 12	ENSP00000365380.4
FOXP3	ENST00000518685.6	TSL:1	c.434C>T	p.Ala145Val	missense	Exon 3 of 10	ENSP00000428952.2
FOXP3	ENST00000557224.6	TSL:2	c.329C>T	p.Ala110Val	missense	Exon 3 of 10	ENSP00000451208.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1029808

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

330244

African (AFR)

AF:

0.00

AC:

AN:

24024

American (AMR)

AF:

0.00

AC:

AN:

24521

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14929

East Asian (EAS)

AF:

0.00

AC:

AN:

29535

South Asian (SAS)

AF:

0.00

AC:

AN:

44192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37865

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3297

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

808432

Other (OTH)

AF:

0.00

AC:

AN:

43013

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome

Pathogenic:1

Sep 05, 2014

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.42

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.27

MetaSVM

Uncertain

0.73

MutationAssessor

Benign

0.97

PhyloP100

5.5

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.0

REVEL

Benign

0.29

Sift

Uncertain

0.014

Sift4G

Benign

0.38

Polyphen

0.98

Vest4

0.30

MutPred

0.24

Gain of sheet (P = 0.0221)

MVP

0.92

MPC

0.63

ClinPred

0.75

GERP RS

5.1

Varity_R

0.26

gMVP

0.36

Mutation Taster

=81/19

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.85

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.85

Position offset: 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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over