rs2232368

Positions:

• chrX-49255822-C-T

Variant summary

Our verdict is Benign. Variant got -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:3
• Conservation: PhyloP100: 0.366

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP3	NM_014009.4	c.648-20G>A		intron_variant		ENST00000376207.10
FOXP3	NM_001114377.2	c.543-20G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP3	ENST00000376207.10	c.648-20G>A		intron_variant		1	NM_014009.4	P1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 1596 AN: 111837 Hom.: 17 Cov.: 23 AF XY: 0.0133 AC XY: 452 AN XY: 34015

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

GnomAD3 exomes AF: 0.0232 AC: 3640 AN: 156851 Hom.: 80 AF XY: 0.0197 AC XY: 953 AN XY: 48485

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 SAS exome AF: 0.00685

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

Gnomad4 AFR exome AF: 0.00271

Gnomad4 AMR exome AF: 0.0804

Gnomad4 ASJ exome AF: 0.000316

Gnomad4 EAS exome AF: 0.0000336

Gnomad4 SAS exome AF: 0.00777

Gnomad4 FIN exome AF: 0.0107

Gnomad4 NFE exome AF: 0.0198

Gnomad4 OTH exome AF: 0.0158

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

Gnomad4 AFR AF: 0.00270

Gnomad4 AMR AF: 0.0531

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000282

Gnomad4 SAS AF: 0.00561

Gnomad4 FIN AF: 0.00832

Gnomad4 NFE AF: 0.0163

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0130 Hom.: 147

Bravo AF: 0.0176

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.6
DANN	Benign	0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs2232368; hg19: chrX-49112283;