rs3761547

Variant names:

• chrX-49262004-T-C
• rs3761547
• NM_014009.4:c.-23+2657A>G

Variant summary

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

The NM_014009.4(FOXP3):​c.-23+2657A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 111,774 control chromosomes in the GnomAD database, including 518 homozygotes. There are 3,393 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 (518 hom., 3393 hem., cov: 23)
• Consequence: FOXP3 NM_014009.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.919
• Publications: 52 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=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP3	NM_014009.4	c.-23+2657A>G		intron_variant	Intron 1 of 11	ENST00000376207.10	NP_054728.2
FOXP3	NM_001114377.2	c.-23+2657A>G		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.-23+2657A>G		intron_variant	Intron 1 of 11	1	NM_014009.4	ENSP00000365380.4
ENSG00000290184	ENST00000703450.1	c.-22-3477A>G		intron_variant	Intron 3 of 3			ENSP00000515301.1

Frequencies

GnomAD3 genomes AF: 0.100 AC: 11184 AN: 111719 Hom.: 514 Cov.: 23

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.0324

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.0910

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.0678

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.0900

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

GnomAD4 genome AF: 0.100 AC: 11198 AN: 111774 Hom.: 518 Cov.: 23 AF XY: 0.0998 AC XY: 3393 AN XY: 33998

African (AFR) AF: 0.0316 AC: 972 AN: 30774

American (AMR) AF: 0.121 AC: 1289 AN: 10653

Ashkenazi Jewish (ASJ) AF: 0.0910 AC: 240 AN: 2638

East Asian (EAS) AF: 0.196 AC: 692 AN: 3523

South Asian (SAS) AF: 0.257 AC: 685 AN: 2664

European-Finnish (FIN) AF: 0.104 AC: 635 AN: 6130

Middle Eastern (MID) AF: 0.0698 AC: 15 AN: 215

European-Non Finnish (NFE) AF: 0.123 AC: 6505 AN: 52979

Other (OTH) AF: 0.0941 AC: 143 AN: 1519

Alfa AF: 0.111 Hom.: 5211

Bravo AF: 0.0957

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.4
DANN	Benign	0.58
PhyloP100		-0.92
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: rs3761547; hg19: chrX-49118461;