rs1057524899

Variant names:

• chrX-49257472-C-T
• rs1057524899
• NM_014009.4:c.409G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_014009.4(FOXP3):​c.409G>A​(p.Ala137Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000483 in 1,035,431 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000048 (0 hom. 1 hem.)
• Consequence: FOXP3 NM_014009.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.401
• Publications: 0 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_014009.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13220417).

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.409G>A	p.Ala137Thr	missense	Exon 4 of 12	NP_054728.2
	FOXP3	NM_001114377.2		c.304G>A	p.Ala102Thr	missense	Exon 3 of 11	NP_001107849.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP3	ENST00000376207.10	TSL:1 MANE Select	c.409G>A	p.Ala137Thr	missense	Exon 4 of 12	ENSP00000365380.4
	FOXP3	ENST00000518685.6	TSL:1	c.409G>A	p.Ala137Thr	missense	Exon 3 of 10	ENSP00000428952.2
	FOXP3	ENST00000557224.6	TSL:2	c.304G>A	p.Ala102Thr	missense	Exon 3 of 10	ENSP00000451208.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000483 AC: 5 AN: 1035431 Hom.: 0 Cov.: 32 AF XY: 0.00000302 AC XY: 1 AN XY: 330943

African (AFR) AF: 0.00 AC: 0 AN: 24586

American (AMR) AF: 0.00 AC: 0 AN: 26911

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15266

East Asian (EAS) AF: 0.00 AC: 0 AN: 29570

South Asian (SAS) AF: 0.00 AC: 0 AN: 44822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37995

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3542

European-Non Finnish (NFE) AF: 0.00000494 AC: 4 AN: 809491

Other (OTH) AF: 0.0000231 AC: 1 AN: 43248

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Insulin-dependent diabetes mellitus secretory diarrhea syndrome (2)
-	1	-	Monogenic diabetes (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.20
DANN	Benign	0.77
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	-0.023	T
MutationAssessor	Benign	0.26	N
PhyloP100		-0.40
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.26
Sift	Benign	0.34	T
Sift4G	Benign	0.36	T
Polyphen		0.015	B
Vest4		0.11
MutPred		0.63		Gain of relative solvent accessibility (P = 0.0023)
MVP		0.67
MPC		0.36
ClinPred		0.062	T
GERP RS		-2.5
Varity_R		0.042
gMVP		0.16
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1057524899; hg19: chrX-49113929;