X-49251352-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_014009.4(FOXP3):c.1278C>A(p.Asn426Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,208,347 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 71 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N426S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.00016 ( 0 hom. 71 hem. )

Consequence

FOXP3
NM_014009.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.504

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14321199).

BP6

Variant X-49251352-G-T is Benign according to our data. Variant chrX-49251352-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1170901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAdExome at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP3	NM_014009.4 linkuse as main transcript	c.1278C>A	p.Asn426Lys	missense_variant	12/12	ENST00000376207.10
FOXP3	NM_001114377.2 linkuse as main transcript	c.1173C>A	p.Asn391Lys	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP3	ENST00000376207.10 linkuse as main transcript	c.1278C>A	p.Asn426Lys	missense_variant	12/12	1	NM_014009.4	P1	Q9BZS1-1

Frequencies

GnomAD3 genomes

AF:

0.000107

AC:

AN:

112077

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34279

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000226

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000850

AC:

AN:

176561

Hom.:

AF XY:

0.0000969

AC XY:

AN XY:

61891

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000652

Gnomad NFE exome

AF:

0.000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000162

AC:

178

AN:

1096270

Hom.:

Cov.:

AF XY:

0.000196

AC XY:

AN XY:

361876

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

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:

0.0000990

Gnomad4 NFE exome

AF:

0.000202

Gnomad4 OTH exome

AF:

0.0000652

GnomAD4 genome

AF:

0.000107

AC:

AN:

112077

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34279

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000226

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.000162

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.24

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.50

D;.;T;.;.;.

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.83

T;T;T;T;.;T

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.14

T;T;T;T;T;T

MetaSVM

Uncertain

0.47

MutationAssessor

Benign

0.81

L;.;.;.;.;.

MutationTaster

Benign

0.78

D;D;N;N;N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.3

N;N;.;N;N;N

REVEL

Benign

0.19

Sift

Uncertain

0.0060

D;D;.;D;D;D

Sift4G

Uncertain

0.017

D;D;T;D;D;D

Polyphen

0.17

B;B;P;P;B;.

Vest4

0.10

MutPred

0.30

Gain of methylation at N426 (P = 0.0021);.;.;.;.;.;

MVP

0.86

MPC

0.62

ClinPred

0.067

GERP RS

2.7

Varity_R

0.16

gMVP

0.66

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