dbSNP rs782528935: 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

FOXP3 links:

Genome browser will be placed here

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

Sel.	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	Q9BZS1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXP3	ENST00000376207.10	TSL:1 MANE Select	c.434C>T	p.Ala145Val	missense	Exon 4 of 12	ENSP00000365380.4	Q9BZS1-1
FOXP3	ENST00000518685.6	TSL:1	c.434C>T	p.Ala145Val	missense	Exon 3 of 10	ENSP00000428952.2	Q9BZS1-4
FOXP3	ENST00000557224.6	TSL:2	c.329C>T	p.Ala110Val	missense	Exon 3 of 10	ENSP00000451208.1	Q9BZS1-3

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

ClinVar submissions

Significance:Likely pathogenic

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

0.12

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

Computational scores

Splicing

Publications

Other links and lift over