X-49257447-G-A

Position:

• chrX-49257447-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_014009.4(FOXP3):​c.434C>T​(p.Ala145Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: FOXP3 NM_014009.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.54

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-49257447-G-A is Pathogenic according to our data. Variant chrX-49257447-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 211045.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP3	NM_014009.4	c.434C>T	p.Ala145Val	missense_variant	4/12	ENST00000376207.10
FOXP3	NM_001114377.2	c.329C>T	p.Ala110Val	missense_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP3	ENST00000376207.10	c.434C>T	p.Ala145Val	missense_variant	4/12	1	NM_014009.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1029808 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 330244

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 05, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T;.;T;.;.;.
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.92	D;D;D;D;.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.27	T;T;T;T;T;T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	0.97	L;.;.;.;.;.
MutationTaster	Benign	0.79	N;N;N;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N
REVEL	Benign	0.29
Sift	Uncertain	0.014	D;D;D;D;D;D
Sift4G	Benign	0.38	T;T;T;T;T;T
Polyphen		0.98	D;D;D;D;D;.
Vest4		0.30
MutPred		0.24		Gain of sheet (P = 0.0221);.;Gain of sheet (P = 0.0221);.;.;.;
MVP		0.92
MPC		0.63
ClinPred		0.75	D
GERP RS		5.1
Varity_R		0.26
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.85		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs782528935; hg19: chrX-49113904;