dbSNP rs122467174: 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:

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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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP3	NM_014009.4 link	c.3G>A	p.Met1?	start_lost	Exon 2 of 12	ENST00000376207.10	NP_054728.2
FOXP3	NM_001114377.2 link	c.3G>A	p.Met1?	start_lost	Exon 2 of 11		NP_001107849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP3	ENST00000376207.10 link	c.3G>A	p.Met1?	start_lost	Exon 2 of 12	1	NM_014009.4	ENSP00000365380.4
ENSG00000290184	ENST00000703450.1 link	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 v4.3

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

T;.;T;.;.

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.90

D;D;D;D;.

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.2

PhyloP100

2.2

PROVEAN

Benign

-1.3

N;N;N;N;N

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Uncertain

0.025

D;D;D;D;D

Polyphen

0.94

P;D;P;P;D

Vest4

0.91

MutPred

0.97

Loss of solvent accessibility (P = 0.0606);Loss of solvent accessibility (P = 0.0606);Loss of solvent accessibility (P = 0.0606);Loss of solvent accessibility (P = 0.0606);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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over