X-49258394-C-T

Variant names:

• chrX-49258394-C-T
• rs782239006
• NM_014009.4:c.112G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000376207.10(FOXP3):​c.112G>A​(p.Ala38Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000513 in 1,170,523 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A38S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.0000038 (0 hom. 1 hem.)
• Consequence: FOXP3 ENST00000376207.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.86
• Publications: 5 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03909281).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000376207.10. 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.112G>A	p.Ala38Thr	missense	Exon 2 of 12	NP_054728.2
	FOXP3	NM_001114377.2		c.112G>A	p.Ala38Thr	missense	Exon 2 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.112G>A	p.Ala38Thr	missense	Exon 2 of 12	ENSP00000365380.4
	FOXP3	ENST00000518685.6	TSL:1	c.112G>A	p.Ala38Thr	missense	Exon 1 of 10	ENSP00000428952.2
	ENSG00000290184	ENST00000703450.1		c.112G>A	p.Ala38Thr	missense	Exon 4 of 4	ENSP00000515301.1

Frequencies

GnomAD3 genomes AF: 0.0000177 AC: 2 AN: 112688 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

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

GnomAD4 exome AF: 0.00000378 AC: 4 AN: 1057835 Hom.: 0 Cov.: 30 AF XY: 0.00000290 AC XY: 1 AN XY: 344717

African (AFR) AF: 0.00 AC: 0 AN: 25391

American (AMR) AF: 0.00 AC: 0 AN: 28529

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18670

East Asian (EAS) AF: 0.00 AC: 0 AN: 27858

South Asian (SAS) AF: 0.00 AC: 0 AN: 50160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4069

European-Non Finnish (NFE) AF: 0.00000487 AC: 4 AN: 820954

Other (OTH) AF: 0.00 AC: 0 AN: 44502

GnomAD4 genome AF: 0.0000177 AC: 2 AN: 112688 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34846

African (AFR) AF: 0.00 AC: 0 AN: 31018

American (AMR) AF: 0.00 AC: 0 AN: 10766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3565

South Asian (SAS) AF: 0.00 AC: 0 AN: 2772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6232

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

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53238

Other (OTH) AF: 0.00 AC: 0 AN: 1515

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.081
DANN	Benign	0.68
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	-0.14	N
PhyloP100		-2.9
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.21
Sift	Benign	0.48	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.054
MutPred		0.14		Gain of relative solvent accessibility (P = 0.0082)
MVP		0.57
MPC		0.35
ClinPred		0.071	T
GERP RS		-8.9
PromoterAI		-0.036	Neutral
Varity_R		0.039
gMVP		0.076
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs782239006; hg19: chrX-49114851;