rs2232364

Variant names:

• chrX-49259888-G-A
• rs2232364
• NM_014009.4:c.-22-1361C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_014009.4(FOXP3):​c.-22-1361C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00564 in 111,413 control chromosomes in the GnomAD database, including 3 homozygotes. There are 155 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0056 (3 hom., 155 hem., cov: 22)
• Consequence: FOXP3 NM_014009.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• Publications: 5 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

ENSG00000290184 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00564 (628/111413) while in subpopulation AFR AF = 0.02 (610/30570). AF 95% confidence interval is 0.0186. There are 3 homozygotes in GnomAd4. There are 155 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.-22-1361C>T		intron	N/A	NP_054728.2
	FOXP3	NM_001114377.2		c.-22-1361C>T		intron	N/A	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.-22-1361C>T		intron	N/A	ENSP00000365380.4	Q9BZS1-1
	ENSG00000290184	ENST00000703450.1		c.-22-1361C>T		intron	N/A	ENSP00000515301.1	A0A494C1K1
	FOXP3	ENST00000557224.6	TSL:2	c.-22-1361C>T		intron	N/A	ENSP00000451208.1	Q9BZS1-3

Frequencies

GnomAD3 genomes AF: 0.00560 AC: 624 AN: 111361 Hom.: 3 Cov.: 22

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000951

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000375

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00467

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00564 AC: 628 AN: 111413 Hom.: 3 Cov.: 22 AF XY: 0.00460 AC XY: 155 AN XY: 33665

African (AFR) AF: 0.0200 AC: 610 AN: 30570

American (AMR) AF: 0.000950 AC: 10 AN: 10524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3555

South Asian (SAS) AF: 0.000376 AC: 1 AN: 2660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5967

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53066

Other (OTH) AF: 0.00461 AC: 7 AN: 1518

Alfa AF: 0.00600 Hom.: 17

Bravo AF: 0.00651

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.028
DANN	Benign	0.48
PhyloP100		-1.5
Mutation Taster		=100/0	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: rs2232364; hg19: chrX-49116345;