X-49251681-G-C

Variant names:

• chrX-49251681-G-C
• rs1557115591
• NM_014009.4:c.1129C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_014009.4(FOXP3):​c.1129C>G​(p.His377Asp) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FOXP3 NM_014009.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_014009.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3323757).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP3	NM_014009.4	c.1129C>G	p.His377Asp	missense_variant	Exon 11 of 12	ENST00000376207.10	NP_054728.2
FOXP3	NM_001114377.2	c.1024C>G	p.His342Asp	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.1129C>G	p.His377Asp	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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome Uncertain:1

Jan 20, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine with aspartic acid at codon 377 of the FOXP3 protein (p.His377Asp). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FOXP3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;.;T;.;.;.
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D;D;D;D;.;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.33	T;T;T;T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	-0.40	N;.;.;.;.;.
PhyloP100		4.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.6	N;N;.;N;N;N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	D;D;.;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D
Polyphen		0.92	P;P;D;P;P;.
Vest4		0.36
MutPred		0.48		Loss of MoRF binding (P = 0.0437);.;.;.;.;.;
MVP		0.91
MPC		1.3
ClinPred		0.94	D
GERP RS		4.4
Varity_R		0.61
gMVP		0.98
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs1557115591; hg19: chrX-49108142;