rs2232368

Variant names:

• chrX-49255822-C-T
• rs2232368
• NM_014009.4:c.648-20G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014009.4(FOXP3):​c.648-20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,177,354 control chromosomes in the GnomAD database, including 244 homozygotes. There are 6,819 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (18 hom., 454 hem., cov: 23)
  • Exomes 𝑓: 0.019 (226 hom. 6365 hem.)
• Consequence: FOXP3 NM_014009.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.366
• Publications: 12 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: G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-49255822-C-T is Benign according to our data. Variant chrX-49255822-C-T is described in ClinVar as Benign. ClinVar VariationId is 1170241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0779 is higher than 0.05.

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.648-20G>A		intron	N/A	NP_054728.2
	FOXP3	NM_001114377.2		c.543-20G>A		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.648-20G>A		intron	N/A	ENSP00000365380.4	Q9BZS1-1
	FOXP3	ENST00000518685.6	TSL:1	c.648-20G>A		intron	N/A	ENSP00000428952.2	Q9BZS1-4
	FOXP3	ENST00000557224.6	TSL:2	c.543-20G>A		intron	N/A	ENSP00000451208.1	Q9BZS1-3

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 1596 AN: 111837 Hom.: 17 Cov.: 23

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.00597

Gnomad FIN AF: 0.00832

Gnomad MID AF: 0.00847

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0133

GnomAD2 exomes AF: 0.0232 AC: 3640 AN: 156851 AF XY: 0.0197

Gnomad AFR exome AF: 0.00268

Gnomad AMR exome AF: 0.0843

Gnomad ASJ exome AF: 0.000287

Gnomad EAS exome AF: 0.0000798

Gnomad FIN exome AF: 0.0112

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0192 AC: 20480 AN: 1065464 Hom.: 226 Cov.: 28 AF XY: 0.0190 AC XY: 6365 AN XY: 334816

African (AFR) AF: 0.00271 AC: 70 AN: 25815

American (AMR) AF: 0.0804 AC: 2690 AN: 33451

Ashkenazi Jewish (ASJ) AF: 0.000316 AC: 6 AN: 18970

East Asian (EAS) AF: 0.0000336 AC: 1 AN: 29760

South Asian (SAS) AF: 0.00777 AC: 401 AN: 51607

European-Finnish (FIN) AF: 0.0107 AC: 423 AN: 39453

Middle Eastern (MID) AF: 0.00395 AC: 16 AN: 4054

European-Non Finnish (NFE) AF: 0.0198 AC: 16160 AN: 817291

Other (OTH) AF: 0.0158 AC: 713 AN: 45063

GnomAD4 genome AF: 0.0143 AC: 1604 AN: 111890 Hom.: 18 Cov.: 23 AF XY: 0.0133 AC XY: 454 AN XY: 34078

African (AFR) AF: 0.00270 AC: 83 AN: 30779

American (AMR) AF: 0.0531 AC: 562 AN: 10585

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.000282 AC: 1 AN: 3543

South Asian (SAS) AF: 0.00561 AC: 15 AN: 2672

European-Finnish (FIN) AF: 0.00832 AC: 51 AN: 6128

Middle Eastern (MID) AF: 0.00930 AC: 2 AN: 215

European-Non Finnish (NFE) AF: 0.0163 AC: 867 AN: 53123

Other (OTH) AF: 0.0132 AC: 20 AN: 1518

Alfa AF: 0.0130 Hom.: 147

Bravo AF: 0.0176

ClinVar

ClinVar submissions

Significance: Benign

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
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.6
DANN	Benign	0.78
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2232368;

hg19: chrX-49112283;