Genetic Variant FOXP3:p.Met1? (chrX-49258503-C-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_014009.4(FOXP3):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

FOXP3
NM_014009.4 start_lost

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.20

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

FOXP3 links:

ENSG00000290184 (HGNC:):

ENSG00000290184 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 64 codons. Genomic position: 49258316. Lost 0.147 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-49258503-C-T is Pathogenic according to our data. Variant chrX-49258503-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 11418.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014009.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP3	NM_014009.4	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 2 of 12	NP_054728.2
	FOXP3	NM_001114377.2		c.3G>A	p.Met1?	start_lost	Exon 2 of 11	NP_001107849.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FOXP3	ENST00000376207.10	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 2 of 12	ENSP00000365380.4
FOXP3	ENST00000518685.6	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 1 of 10	ENSP00000428952.2
ENSG00000290184	ENST00000703450.1		c.3G>A	p.Met1?	start_lost	Exon 4 of 4	ENSP00000515301.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1052586

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

333870

African (AFR)

AF:

0.00

AC:

AN:

25280

American (AMR)

AF:

0.00

AC:

AN:

28805

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17710

East Asian (EAS)

AF:

0.00

AC:

AN:

28919

South Asian (SAS)

AF:

0.00

AC:

AN:

48551

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37748

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3872

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

817679

Other (OTH)

AF:

0.00

AC:

AN:

44022

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome

Pathogenic:1

Jun 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.74

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.2

PhyloP100

2.2

PROVEAN

Benign

-1.3

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.025

Polyphen

0.94

Vest4

0.91

MutPred

0.97

Loss of solvent accessibility (P = 0.0606)

MVP

0.99

ClinPred

0.95

GERP RS

4.5

PromoterAI

-0.025

Neutral

(source)

Varity_R

0.92

gMVP

0.24

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over