rs587780340

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014009.4(FOXP3):c.157G>A(p.Gly53Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000326 in 1,165,373 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000033 ( 0 hom. 13 hem. )

Consequence

FOXP3
NM_014009.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.24

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_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25330082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP3	NM_014009.4 linkuse as main transcript	c.157G>A	p.Gly53Arg	missense_variant	2/12	ENST00000376207.10
FOXP3	NM_001114377.2 linkuse as main transcript	c.157G>A	p.Gly53Arg	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP3	ENST00000376207.10 linkuse as main transcript	c.157G>A	p.Gly53Arg	missense_variant	2/12	1	NM_014009.4	P1	Q9BZS1-1

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112365

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34529

show subpopulations

Gnomad AFR

AF:

0.0000323

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000883

AC:

AN:

113297

Hom.:

AF XY:

0.0000251

AC XY:

AN XY:

39863

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:

0.00

Gnomad NFE exome

AF:

0.0000232

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000332

AC:

AN:

1052954

Hom.:

Cov.:

AF XY:

0.0000378

AC XY:

AN XY:

343772

show subpopulations

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:

0.0000201

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000415

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112419

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34593

show subpopulations

Gnomad4 AFR

AF:

0.0000323

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:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 16, 2013

- -

Insulin-dependent diabetes mellitus secretory diarrhea syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2022

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 not expected to disrupt FOXP3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 129110). This variant has not been reported in the literature in individuals affected with FOXP3-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 53 of the FOXP3 protein (p.Gly53Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.34

T;.;T;.;.;.

FATHMM_MKL

Benign

0.17

LIST_S2

Uncertain

0.90

D;D;D;D;.;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.25

T;T;T;T;T;T

MetaSVM

Uncertain

0.61

MutationAssessor

Benign

0.90

L;L;.;L;L;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.80

N;N;N;N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.035

D;D;D;D;D;D

Sift4G

Benign

0.55

T;T;T;T;T;T

Polyphen

1.0

D;D;D;D;D;.

Vest4

0.22

MutPred

0.42

Gain of methylation at G53 (P = 0.0075);Gain of methylation at G53 (P = 0.0075);Gain of methylation at G53 (P = 0.0075);Gain of methylation at G53 (P = 0.0075);Gain of methylation at G53 (P = 0.0075);.;

MVP

0.86

MPC

0.69

ClinPred

0.23

GERP RS

4.5

Varity_R

0.10

gMVP

0.16

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