dbSNP rs782528935: FOXP3:p.Ala145Val (chrX-49257447-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius 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 id is 211045.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP3	NM_014009.4 link	c.434C>T	p.Ala145Val	missense_variant	Exon 4 of 12	ENST00000376207.10	NP_054728.2	Q9BZS1-1
FOXP3	NM_001114377.2 link	c.329C>T	p.Ala110Val	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.434C>T	p.Ala145Val	missense_variant	Exon 4 of 12	1	NM_014009.4	ENSP00000365380.4		Q9BZS1-1

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.42

T;.;T;.;.;.

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.92

D;D;D;D;.;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.27

T;T;T;T;T;T

MetaSVM

Uncertain

0.73

MutationAssessor

Benign

0.97

L;.;.;.;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.0

N;N;N;N;N;N

REVEL

Benign

0.29

Sift

Uncertain

0.014

D;D;D;D;D;D

Sift4G

Benign

0.38

T;T;T;T;T;T

Polyphen

0.98

D;D;D;D;D;.

Vest4

0.30

MutPred

0.24

Gain of sheet (P = 0.0221);.;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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over