X-49259633-C-T

Variant names:

• chrX-49259633-C-T
• rs12843496
• NM_014009.4:c.-22-1106G>A

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.-22-1106G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00467 in 110,842 control chromosomes in the GnomAD database, including 2 homozygotes. There are 108 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 0.0047 (2 hom., 108 hem., cov: 22)
• Consequence: FOXP3 NM_014009.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.821
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

ENSG00000290184 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00467 (518/110842) while in subpopulation NFE AF = 0.00777 (411/52878). AF 95% confidence interval is 0.00715. There are 2 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP3	NM_014009.4	MANE Select	c.-22-1106G>A		intron	N/A	NP_054728.2
	FOXP3	NM_001114377.2		c.-22-1106G>A		intron	N/A	NP_001107849.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP3	ENST00000376207.10	TSL:1 MANE Select	c.-22-1106G>A		intron	N/A	ENSP00000365380.4
	ENSG00000290184	ENST00000703450.1		c.-22-1106G>A		intron	N/A	ENSP00000515301.1
	FOXP3	ENST00000557224.6	TSL:2	c.-22-1106G>A		intron	N/A	ENSP00000451208.1

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 519 AN: 110787 Hom.: 2 Cov.: 22

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00588

Gnomad AMR AF: 0.00279

Gnomad ASJ AF: 0.00683

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000773

Gnomad FIN AF: 0.000338

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.00777

Gnomad OTH AF: 0.00600

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

GnomAD4 genome AF: 0.00467 AC: 518 AN: 110842 Hom.: 2 Cov.: 22 AF XY: 0.00327 AC XY: 108 AN XY: 33042

African (AFR) AF: 0.00131 AC: 40 AN: 30477

American (AMR) AF: 0.00278 AC: 29 AN: 10424

Ashkenazi Jewish (ASJ) AF: 0.00683 AC: 18 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3513

South Asian (SAS) AF: 0.000775 AC: 2 AN: 2581

European-Finnish (FIN) AF: 0.000338 AC: 2 AN: 5919

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 217

European-Non Finnish (NFE) AF: 0.00777 AC: 411 AN: 52878

Other (OTH) AF: 0.00593 AC: 9 AN: 1518

Alfa AF: 0.00434 Hom.: 74

Bravo AF: 0.00496

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.5
DANN	Benign	0.76
PhyloP100		0.82
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs12843496; hg19: chrX-49116090;