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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014009.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP3	NM_014009.4	MANE Select	c.970T>G	p.Phe324Val	missense splice_region	Exon 10 of 12	NP_054728.2
	FOXP3	NM_001114377.2		c.865T>G	p.Phe289Val	missense splice_region	Exon 9 of 11	NP_001107849.1	Q9BZS1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP3	ENST00000376207.10	TSL:1 MANE Select	c.970T>G	p.Phe324Val	missense splice_region	Exon 10 of 12	ENSP00000365380.4	Q9BZS1-1
	FOXP3	ENST00000518685.6	TSL:1	c.889T>G	p.Phe297Val	missense splice_region	Exon 8 of 10	ENSP00000428952.2	Q9BZS1-4
	FOXP3	ENST00000557224.6	TSL:2	c.865T>G	p.Phe289Val	missense splice_region	Exon 9 of 10	ENSP00000451208.1	Q9BZS1-3

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Insulin-dependent diabetes mellitus secretory diarrhea syndrome (2)
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.30
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.010	N
REVEL	Uncertain	0.58
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.050	T
Polyphen		0.062	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;