NM_014009.4:c.773C>T

Variant names:

• chrX-49255472-G-A
• rs369698589
• NM_014009.4:c.773C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_014009.4(FOXP3):​c.773C>T​(p.Ala258Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000325 in 1,201,586 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000033 (0 hom. 14 hem.)
• Consequence: FOXP3 NM_014009.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66
• Publications: 2 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP3	NM_014009.4	MANE Select	c.773C>T	p.Ala258Val	missense	Exon 8 of 12	NP_054728.2
	FOXP3	NM_001114377.2		c.668C>T	p.Ala223Val	missense	Exon 7 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.773C>T	p.Ala258Val	missense	Exon 8 of 12	ENSP00000365380.4	Q9BZS1-1
	FOXP3	ENST00000518685.6	TSL:1	c.735+243C>T		intron	N/A	ENSP00000428952.2	Q9BZS1-4
	FOXP3	ENST00000557224.6	TSL:2	c.668C>T	p.Ala223Val	missense	Exon 7 of 10	ENSP00000451208.1	Q9BZS1-3

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 3 AN: 112467 Hom.: 0 Cov.: 23

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: 0.00000613 AC: 1 AN: 163221 AF XY: 0.0000192

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: 0.0000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000331 AC: 36 AN: 1089119 Hom.: 0 Cov.: 31 AF XY: 0.0000393 AC XY: 14 AN XY: 356227

African (AFR) AF: 0.00 AC: 0 AN: 26275

American (AMR) AF: 0.00 AC: 0 AN: 34231

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19187

East Asian (EAS) AF: 0.00 AC: 0 AN: 29947

South Asian (SAS) AF: 0.00 AC: 0 AN: 52337

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4121

European-Non Finnish (NFE) AF: 0.0000418 AC: 35 AN: 837418

Other (OTH) AF: 0.0000218 AC: 1 AN: 45767

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112467 Hom.: 0 Cov.: 23 AF XY: 0.0000578 AC XY: 2 AN XY: 34603

African (AFR) AF: 0.0000323 AC: 1 AN: 30948

American (AMR) AF: 0.00 AC: 0 AN: 10713

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3546

South Asian (SAS) AF: 0.00 AC: 0 AN: 2758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6225

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53179

Other (OTH) AF: 0.00 AC: 0 AN: 1523

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Insulin-dependent diabetes mellitus secretory diarrhea syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.052	T
Polyphen		1.0	D
Vest4		0.33
MVP		0.98
MPC		1.1
ClinPred		0.80	D
GERP RS		4.6
Varity_R		0.42
gMVP		0.22
Mutation Taster		=84/16	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

Other links and lift over

dbSNP: rs369698589; hg19: chrX-49111933; COSMIC: COSV66052133; COSMIC: COSV66052133;