X-49251441-G-A

Position:

chrX-49251441-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_014009.4(FOXP3):c.1189C>T(p.Arg397Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 112,222 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R397Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

FOXP3
NM_014009.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.18

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 Pathogenic. Variant got 18 ACMG points.

PM1

In a DNA_binding_region Fork-head (size 86) in uniprot entity FOXP3_HUMAN there are 23 pathogenic changes around while only 3 benign (88%) in NM_014009.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-49251440-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 379222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant X-49251441-G-A is Pathogenic according to our data. Variant chrX-49251441-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP3	NM_014009.4 linkuse as main transcript	c.1189C>T	p.Arg397Trp	missense_variant	12/12	ENST00000376207.10
FOXP3	NM_001114377.2 linkuse as main transcript	c.1084C>T	p.Arg362Trp	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP3	ENST00000376207.10 linkuse as main transcript	c.1189C>T	p.Arg397Trp	missense_variant	12/12	1	NM_014009.4	P1	Q9BZS1-1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34396

show subpopulations

Gnomad AFR

AF:

0.0000324

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000547

AC:

AN:

182711

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67315

show subpopulations

Gnomad AFR exome

AF:

0.0000763

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1098073

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363443

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

AF:

0.0000178

AC:

AN:

112222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34396

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000811

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2021	This variant has been observed in individuals with clinical features of IPEX syndrome (PMID: 11137992, 11295725, 25546394, 30293990, 30443250, 31130284). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11407). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 397 of the FOXP3 protein (p.Arg397Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects FOXP3 protein function (PMID: 16920951, 22590469, 28778586, 28783662). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FOXP3 protein function. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	Variant summary: FOXP3 c.1189C>T (p.Arg397Trp) results in a non-conservative amino acid change located in the Fork head domain (IPR001766) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182711 control chromosomes (gnomAD). c.1189C>T has been reported in the literature in multiple individuals affected with Insulin-Dependent Diabetes Mellitus Secretory Diarrhea Syndrome (Wildin_2001, Xavier-DaSilva_2015, Gambineri_2018, Quinlan Jones_2019, Shangaris_2021). These data indicate that the variant is associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hydrops fetalis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics - Synnovis, NHS South East Genomic Laboratory Hub

Mar 02, 2020

This variant detected in two affected male fetuses and not detected in an unaffected male fetus (consecutive pregnancies). The same variant reported by Xavier-da-Silva (2015) in a fetus presenting with hydrops at 27 weeks' gestation and in a term newborn who developed diabetes mellitus during the first hours of life. Levy-Lahad & Wildin (2001) also reported this variant in three siblings presenting with IPEX manifestations at birth. In all previously reported cases, the pathological process began during intrauterine life; furthermore, there are no survivors described. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.66

BayesDel_noAF

Pathogenic

0.71

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;.;D;.;.;.

FATHMM_MKL

Uncertain

0.82

LIST_S2

Pathogenic

0.99

D;D;D;D;.;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

H;.;.;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-7.4

D;D;.;D;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;D;.

Vest4

0.81

MutPred

0.90

Loss of MoRF binding (P = 0.0381);.;.;.;.;.;

MVP

1.0

MPC

1.2

ClinPred

1.0

GERP RS

1.5

Varity_R

0.94

gMVP

0.98

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

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