chrX-49251339-G-A

Variant names:

• chrX-49251339-G-A
• NM_014009.4:c.1291C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014009.4(FOXP3):​c.1291C>T​(p.Pro431Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: 0.927

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3307408).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP3	NM_014009.4	c.1291C>T	p.Pro431Ser	missense_variant	Exon 12 of 12	ENST00000376207.10	NP_054728.2
FOXP3	NM_001114377.2	c.1186C>T	p.Pro396Ser	missense_variant	Exon 11 of 11		NP_001107849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP3	ENST00000376207.10	c.1291C>T	p.Pro431Ser	missense_variant	Exon 12 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

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 431 of the FOXP3 protein (p.Pro431Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FOXP3-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Probably Damaging". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	Benign	0.10
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;T;.;.;.
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.87	D;D;D;D;.;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.33	T;T;T;T;T;T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	0.69	N;.;.;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.15	N;N;.;N;N;N
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D;D;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.036	B;B;D;B;B;.
Vest4		0.19
MutPred		0.23		Gain of phosphorylation at P431 (P = 0.009);.;.;.;.;.;
MVP		0.83
MPC		1.2
ClinPred		0.63	D
GERP RS		3.7
Varity_R		0.099
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-49107800;