rs122467169

Variant names:

• chrX-49251698-A-C
• rs122467169
• NM_014009.4:c.1112T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_014009.4(FOXP3):​c.1112T>G​(p.Phe371Cys) variant causes a missense change. 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: 23)
• Consequence: FOXP3 NM_014009.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.27

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-49251698-A-C is Pathogenic according to our data. Variant chrX-49251698-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 11409.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	c.1112T>G	p.Phe371Cys	missense_variant	Exon 11 of 12	ENST00000376207.10	NP_054728.2
FOXP3	NM_001114377.2	c.1007T>G	p.Phe336Cys	missense_variant	Exon 10 of 11		NP_001107849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP3	ENST00000376207.10	c.1112T>G	p.Phe371Cys	missense_variant	Exon 11 of 12	1	NM_014009.4	ENSP00000365380.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome Pathogenic:1

Jan 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.;D;.;.;.
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.;.;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.5	D;D;.;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;.
Vest4		0.91
MutPred		0.97		Loss of MoRF binding (P = 0.1013);.;.;.;.;.;
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.94
gMVP		0.99

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

Other links and lift over

dbSNP: rs122467169; hg19: chrX-49108159;