rs3761549

Variant names:

• chrX-49260888-G-A
• rs3761549
• NM_014009.4:c.-22-2361C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014009.4(FOXP3):​c.-22-2361C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0997 in 112,246 control chromosomes in the GnomAD database, including 516 homozygotes. There are 3,402 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 0.10 (516 hom., 3402 hem., cov: 24)
• Consequence: FOXP3 NM_014009.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.889
• Publications: 88 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=-0.68).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP3	NM_014009.4	c.-22-2361C>T		intron_variant	Intron 1 of 11	ENST00000376207.10	NP_054728.2
FOXP3	NM_001114377.2	c.-22-2361C>T		intron_variant	Intron 1 of 10		NP_001107849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP3	ENST00000376207.10	c.-22-2361C>T		intron_variant	Intron 1 of 11	1	NM_014009.4	ENSP00000365380.4
ENSG00000290184	ENST00000703450.1	c.-22-2361C>T		intron_variant	Intron 3 of 3			ENSP00000515301.1

Frequencies

GnomAD3 genomes AF: 0.0996 AC: 11173 AN: 112190 Hom.: 512 Cov.: 24

Gnomad AFR AF: 0.0315

Gnomad AMI AF: 0.0366

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0897

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0636

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.0914

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

GnomAD4 genome AF: 0.0997 AC: 11187 AN: 112246 Hom.: 516 Cov.: 24 AF XY: 0.0988 AC XY: 3402 AN XY: 34442

African (AFR) AF: 0.0314 AC: 974 AN: 31021

American (AMR) AF: 0.120 AC: 1289 AN: 10714

Ashkenazi Jewish (ASJ) AF: 0.0897 AC: 238 AN: 2653

East Asian (EAS) AF: 0.191 AC: 670 AN: 3513

South Asian (SAS) AF: 0.256 AC: 690 AN: 2693

European-Finnish (FIN) AF: 0.103 AC: 628 AN: 6124

Middle Eastern (MID) AF: 0.0651 AC: 14 AN: 215

European-Non Finnish (NFE) AF: 0.123 AC: 6512 AN: 53090

Other (OTH) AF: 0.0955 AC: 147 AN: 1540

Alfa AF: 0.107 Hom.: 4666

Bravo AF: 0.0955

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	13
DANN	Benign	0.70
PhyloP100		0.89
Mutation Taster		=100/0	polymorphism (auto)

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: rs3761549; hg19: chrX-49117345;