rs587780340

Variant names:

• chrX-49258349-C-T
• rs587780340
• NM_014009.4:c.157G>A
• FOXP3 p.Gly53Arg

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014009.4(FOXP3):​c.157G>A​(p.Gly53Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000326 in 1,165,373 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000033 (0 hom. 13 hem.)
• Consequence: FOXP3 NM_014009.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.24
• Publications: 3 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: G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000290184 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25330082).
• BS2: High Hemizygotes in GnomAdExome4 at 13 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP3	NM_014009.4	MANE Select	c.157G>A	p.Gly53Arg	missense	Exon 2 of 12	NP_054728.2
	FOXP3	NM_001114377.2		c.157G>A	p.Gly53Arg	missense	Exon 2 of 11	NP_001107849.1	Q9BZS1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP3	ENST00000376207.10	TSL:1 MANE Select	c.157G>A	p.Gly53Arg	missense	Exon 2 of 12	ENSP00000365380.4	Q9BZS1-1
	FOXP3	ENST00000518685.6	TSL:1	c.157G>A	p.Gly53Arg	missense	Exon 1 of 10	ENSP00000428952.2	Q9BZS1-4
	ENSG00000290184	ENST00000703450.1		c.157G>A	p.Gly53Arg	missense	Exon 4 of 4	ENSP00000515301.1	A0A494C1K1

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 3 AN: 112365 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000883 AC: 1 AN: 113297 AF XY: 0.0000251

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000232

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000332 AC: 35 AN: 1052954 Hom.: 0 Cov.: 30 AF XY: 0.0000378 AC XY: 13 AN XY: 343772

African (AFR) AF: 0.00 AC: 0 AN: 24936

American (AMR) AF: 0.00 AC: 0 AN: 27858

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18607

East Asian (EAS) AF: 0.00 AC: 0 AN: 27154

South Asian (SAS) AF: 0.0000201 AC: 1 AN: 49816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4064

European-Non Finnish (NFE) AF: 0.0000415 AC: 34 AN: 818703

Other (OTH) AF: 0.00 AC: 0 AN: 44334

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112419 Hom.: 0 Cov.: 24 AF XY: 0.0000289 AC XY: 1 AN XY: 34593

African (AFR) AF: 0.0000323 AC: 1 AN: 30992

American (AMR) AF: 0.00 AC: 0 AN: 10749

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3542

South Asian (SAS) AF: 0.00 AC: 0 AN: 2735

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6177

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53153

Other (OTH) AF: 0.00 AC: 0 AN: 1528

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	0.90	L
PhyloP100		2.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.37
Sift	Benign	0.035	D
Sift4G	Benign	0.55	T
PromoterAI		0.023	Neutral
Varity_R		0.10
gMVP		0.16
Mutation Taster		=88/12	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587780340;

hg19: chrX-49114806;