rs122467173

Variant names:

• chrX-49253200-A-C
• rs122467173
• NM_014009.4:c.970T>G

Your query was ambiguous. Multiple possible variants found:

• chrX-49253200-A-C
• chrX-49253200-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_014009.4(FOXP3):​c.970T>G​(p.Phe324Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,093,706 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F324L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: FOXP3 NM_014009.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.298
• Publications: 10 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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-49253200-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11416.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31757903).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP3	NM_014009.4	c.970T>G	p.Phe324Val	missense_variant, splice_region_variant	Exon 10 of 12	ENST00000376207.10	NP_054728.2
FOXP3	NM_001114377.2	c.865T>G	p.Phe289Val	missense_variant, splice_region_variant	Exon 9 of 11		NP_001107849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP3	ENST00000376207.10	c.970T>G	p.Phe324Val	missense_variant, splice_region_variant	Exon 10 of 12	1	NM_014009.4	ENSP00000365380.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1093706 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 359316

African (AFR) AF: 0.0000760 AC: 2 AN: 26317

American (AMR) AF: 0.00 AC: 0 AN: 35045

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19318

East Asian (EAS) AF: 0.00 AC: 0 AN: 30108

South Asian (SAS) AF: 0.00 AC: 0 AN: 53461

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40367

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839043

Other (OTH) AF: 0.00 AC: 0 AN: 45924

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FOXP3: PM2 -

Feb 04, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Insulin-dependent diabetes mellitus secretory diarrhea syndrome Uncertain:2

May 27, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1677891). This variant has not been reported in the literature in individuals affected with FOXP3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 324 of the FOXP3 protein (p.Phe324Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T;.;T;.;.;.
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.86	D;D;D;D;.;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.32	T;T;T;T;T;T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.
PhyloP100		0.30
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.010	N;N;D;N;N;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.026	D;D;D;D;D;D
Sift4G	Uncertain	0.050	T;T;T;T;T;T
Polyphen		0.062	B;B;B;P;B;.
Vest4		0.22
MutPred		0.34		Gain of catalytic residue at F324 (P = 0.0578);.;.;.;.;.;
MVP		0.99
MPC		0.54
ClinPred		0.35	T
GERP RS		3.9
Varity_R		0.16
gMVP		0.92
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs122467173; hg19: chrX-49109661;