rs2232367

Variant names:

• chrX-49256855-G-A
• rs2232367
• NM_014009.4:c.543C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014009.4(FOXP3):​c.543C>T​(p.Ser181Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0341 in 1,209,803 control chromosomes in the GnomAD database, including 594 homozygotes. There are 13,451 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.029 (54 hom., 1012 hem., cov: 23)
  • Exomes 𝑓: 0.035 (540 hom. 12439 hem.)
• Consequence: FOXP3 NM_014009.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.03634
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.652
• Publications: 17 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant X-49256855-G-A is Benign according to our data. Variant chrX-49256855-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129111.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0294 (3314/112685) while in subpopulation NFE AF = 0.0408 (2169/53212). AF 95% confidence interval is 0.0393. There are 54 homozygotes in GnomAd4. There are 1012 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 54 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.543C>T	p.Ser181Ser	splice_region synonymous	Exon 6 of 12	NP_054728.2
	FOXP3	NM_001114377.2		c.438C>T	p.Ser146Ser	splice_region synonymous	Exon 5 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.543C>T	p.Ser181Ser	splice_region synonymous	Exon 6 of 12	ENSP00000365380.4	Q9BZS1-1
	FOXP3	ENST00000518685.6	TSL:1	c.543C>T	p.Ser181Ser	splice_region synonymous	Exon 5 of 10	ENSP00000428952.2	Q9BZS1-4
	FOXP3	ENST00000557224.6	TSL:2	c.438C>T	p.Ser146Ser	splice_region synonymous	Exon 5 of 10	ENSP00000451208.1	Q9BZS1-3

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 3314 AN: 112634 Hom.: 54 Cov.: 23

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0300

Gnomad ASJ AF: 0.0826

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.00794

Gnomad FIN AF: 0.0540

Gnomad MID AF: 0.0460

Gnomad NFE AF: 0.0408

Gnomad OTH AF: 0.0324

GnomAD2 exomes AF: 0.0315 AC: 5768 AN: 183213 AF XY: 0.0315

Gnomad AFR exome AF: 0.00510

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.0757

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0502

Gnomad NFE exome AF: 0.0425

Gnomad OTH exome AF: 0.0327

GnomAD4 exome AF: 0.0346 AC: 37948 AN: 1097118 Hom.: 540 Cov.: 31 AF XY: 0.0343 AC XY: 12439 AN XY: 362552

African (AFR) AF: 0.00409 AC: 108 AN: 26386

American (AMR) AF: 0.0151 AC: 530 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.0751 AC: 1456 AN: 19379

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30202

South Asian (SAS) AF: 0.0165 AC: 891 AN: 54113

European-Finnish (FIN) AF: 0.0522 AC: 2113 AN: 40492

Middle Eastern (MID) AF: 0.0486 AC: 201 AN: 4132

European-Non Finnish (NFE) AF: 0.0370 AC: 31122 AN: 841150

Other (OTH) AF: 0.0331 AC: 1525 AN: 46063

GnomAD4 genome AF: 0.0294 AC: 3314 AN: 112685 Hom.: 54 Cov.: 23 AF XY: 0.0290 AC XY: 1012 AN XY: 34851

African (AFR) AF: 0.00559 AC: 174 AN: 31125

American (AMR) AF: 0.0300 AC: 322 AN: 10746

Ashkenazi Jewish (ASJ) AF: 0.0826 AC: 219 AN: 2651

East Asian (EAS) AF: 0.000281 AC: 1 AN: 3555

South Asian (SAS) AF: 0.00832 AC: 23 AN: 2763

European-Finnish (FIN) AF: 0.0540 AC: 335 AN: 6202

Middle Eastern (MID) AF: 0.0505 AC: 11 AN: 218

European-Non Finnish (NFE) AF: 0.0408 AC: 2169 AN: 53212

Other (OTH) AF: 0.0313 AC: 48 AN: 1533

Alfa AF: 0.0377 Hom.: 1554

Bravo AF: 0.0279

EpiCase AF: 0.0456

EpiControl AF: 0.0419

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	1	2	Insulin-dependent diabetes mellitus secretory diarrhea syndrome (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Benign	0.64
PhyloP100		0.65
Mutation Taster		=84/16	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.036
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.19		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: rs2232367; hg19: chrX-49113312; COSMIC: COSV66051368;