NM_014009.4:c.340C>T

Variant names:

• chrX-49257541-G-A
• rs200554980
• NM_014009.4:c.340C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_014009.4(FOXP3):​c.340C>T​(p.Arg114Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000168 in 1,179,256 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 62 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R114Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., 11 hem., cov: 23)
  • Exomes 𝑓: 0.00016 (0 hom. 51 hem.)
• Consequence: FOXP3 NM_014009.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.54
• Publications: 6 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07122582).
• BP6: Variant X-49257541-G-A is Benign according to our data. Variant chrX-49257541-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435256.
• BS2: High Hemizygotes in GnomAd4 at 11 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP3	NM_014009.4	MANE Select	c.340C>T	p.Arg114Trp	missense	Exon 4 of 12	NP_054728.2
	FOXP3	NM_001114377.2		c.235C>T	p.Arg79Trp	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.340C>T	p.Arg114Trp	missense	Exon 4 of 12	ENSP00000365380.4
	FOXP3	ENST00000518685.6	TSL:1	c.340C>T	p.Arg114Trp	missense	Exon 3 of 10	ENSP00000428952.2
	FOXP3	ENST00000557224.6	TSL:2	c.235C>T	p.Arg79Trp	missense	Exon 3 of 10	ENSP00000451208.1

Frequencies

GnomAD3 genomes AF: 0.000214 AC: 24 AN: 111987 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000939

Gnomad ASJ AF: 0.00795

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: 0.000264 AC: 41 AN: 155102 AF XY: 0.000309

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000788

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.0000746

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000731

Gnomad OTH exome AF: 0.000522

GnomAD4 exome AF: 0.000163 AC: 174 AN: 1067269 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 51 AN XY: 343677

African (AFR) AF: 0.00 AC: 0 AN: 25983

American (AMR) AF: 0.0000592 AC: 2 AN: 33757

Ashkenazi Jewish (ASJ) AF: 0.00636 AC: 112 AN: 17599

East Asian (EAS) AF: 0.0000336 AC: 1 AN: 29725

South Asian (SAS) AF: 0.00 AC: 0 AN: 49604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3958

European-Non Finnish (NFE) AF: 0.0000486 AC: 40 AN: 822559

Other (OTH) AF: 0.000425 AC: 19 AN: 44724

GnomAD4 genome AF: 0.000214 AC: 24 AN: 111987 Hom.: 0 Cov.: 23 AF XY: 0.000322 AC XY: 11 AN XY: 34187

African (AFR) AF: 0.00 AC: 0 AN: 30719

American (AMR) AF: 0.0000939 AC: 1 AN: 10652

Ashkenazi Jewish (ASJ) AF: 0.00795 AC: 21 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3551

South Asian (SAS) AF: 0.00 AC: 0 AN: 2709

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6163

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53125

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.000315 Hom.: 12

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000141 AC: 17

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.071	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.90	L
PhyloP100		5.5
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.51
MVP		0.95
MPC		1.0
ClinPred		0.082	T
GERP RS		5.3
Varity_R		0.26
gMVP		0.43
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200554980; hg19: chrX-49113998;