X-49253200-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP5 BP4 BS2

The NM_014009.4(FOXP3):​c.970T>C​(p.Phe324Leu) 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 1,093,705 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F324V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
• Consequence: FOXP3 NM_014009.4 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• 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: Likely_benign. The variant received -4 ACMG points.

• PP5: Variant X-49253200-A-G is Pathogenic according to our data. 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=0.36225215). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

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>C	p.Phe324Leu	missense splice_region	Exon 10 of 12	NP_054728.2
	FOXP3	NM_001114377.2		c.865T>C	p.Phe289Leu	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>C	p.Phe324Leu	missense splice_region	Exon 10 of 12	ENSP00000365380.4	Q9BZS1-1
	FOXP3	ENST00000518685.6	TSL:1	c.889T>C	p.Phe297Leu	missense splice_region	Exon 8 of 10	ENSP00000428952.2	Q9BZS1-4
	FOXP3	ENST00000557224.6	TSL:2	c.865T>C	p.Phe289Leu	missense splice_region	Exon 9 of 10	ENSP00000451208.1	Q9BZS1-3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1093705 Hom.: 0 Cov.: 29 AF XY: 0.00000557 AC XY: 2 AN XY: 359315

African (AFR) AF: 0.00 AC: 0 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: 40366

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

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 839043

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

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Insulin-dependent diabetes mellitus secretory diarrhea syndrome (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.027	D
MutationAssessor	Benign	1.8	L
PhyloP100		0.30
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.44	N
REVEL	Uncertain	0.56
Sift	Benign	0.61	T
Sift4G	Benign	0.75	T
Polyphen		0.0050	B
Vest4		0.12
MutPred		0.30		Gain of disorder (P = 0.1536)
MVP		1.0
MPC		0.48
ClinPred		0.11	T
GERP RS		3.9
Varity_R		0.12
gMVP		0.89
Mutation Taster		=92/8	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs122467173; hg19: chrX-49109661;