Genetic Variant FOXP3:p.Ala38Ser (chrX-49258394-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_014009.4(FOXP3):c.112G>T(p.Ala38Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000372 in 1,170,522 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 125 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.00041 ( 0 hom. 124 hem. )

Consequence

FOXP3
NM_014009.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.86

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:

ENSG00000290184 (HGNC:):

ENSG00000290184 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.058613867).

BP6

Variant X-49258394-C-A is Benign according to our data. Variant chrX-49258394-C-A is described in ClinVar as [Benign]. Clinvar id is 529765.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000407 (431/1057834) while in subpopulation NFE AF= 0.00052 (427/820952). AF 95% confidence interval is 0.000479. There are 0 homozygotes in gnomad4_exome. There are 124 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Hemizygotes in GnomAdExome4 at 124 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP3	NM_014009.4 link	c.112G>T	p.Ala38Ser	missense_variant	Exon 2 of 12	ENST00000376207.10	NP_054728.2	Q9BZS1-1
FOXP3	NM_001114377.2 link	c.112G>T	p.Ala38Ser	missense_variant	Exon 2 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.112G>T	p.Ala38Ser	missense_variant	Exon 2 of 12	1	NM_014009.4	ENSP00000365380.4		Q9BZS1-1
ENSG00000290184	ENST00000703450.1 link	c.112G>T	p.Ala38Ser	missense_variant	Exon 4 of 4			ENSP00000515301.1		A0A494C1K1

Frequencies

GnomAD3 genomes

AF:

0.0000444

AC:

AN:

112688

Hom.:

Cov.:

AF XY:

0.0000287

AC XY:

AN XY:

34846

show subpopulations

Gnomad AFR

AF:

0.0000967

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:

0.0000506

AC:

AN:

118541

Hom.:

AF XY:

0.0000497

AC XY:

AN XY:

40265

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:

0.000108

Gnomad OTH exome

AF:

0.000303

GnomAD4 exome

AF:

0.000407

AC:

431

AN:

1057834

Hom.:

Cov.:

AF XY:

0.000360

AC XY:

124

AN XY:

344716

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000520

Gnomad4 OTH exome

AF:

0.0000899

GnomAD4 genome

AF:

0.0000444

AC:

AN:

112688

Hom.:

Cov.:

AF XY:

0.0000287

AC XY:

AN XY:

34846

show subpopulations

Gnomad4 AFR

AF:

0.0000967

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:

0.0000718

ExAC

AF:

0.0000378

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome

Benign:1

Dec 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.063

DANN

Benign

0.76

DEOGEN2

Benign

0.26

T;.;T;.;.;.

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.84

T;T;T;T;.;T

M_CAP

Benign

0.064

MetaRNN

Benign

0.059

T;T;T;T;T;T

MetaSVM

Uncertain

-0.074

MutationAssessor

Benign

0.55

N;N;.;N;N;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.32

N;N;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.17

T;D;T;D;D;D

Sift4G

Benign

0.31

T;T;T;T;T;T

Polyphen

0.044

B;B;B;B;B;.

Vest4

0.054

MVP

0.73

MPC

0.33

ClinPred

0.058

GERP RS

-8.9

Varity_R

0.059

gMVP

0.070

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