X-49258394-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000376207.10(FOXP3):​c.112G>C​(p.Ala38Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 24)
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06376767).

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>C	p.Ala38Pro	missense	Exon 2 of 12	NP_054728.2
	FOXP3	NM_001114377.2		c.112G>C	p.Ala38Pro	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>C	p.Ala38Pro	missense	Exon 2 of 12	ENSP00000365380.4
	FOXP3	ENST00000518685.6	TSL:1	c.112G>C	p.Ala38Pro	missense	Exon 1 of 10	ENSP00000428952.2
	ENSG00000290184	ENST00000703450.1		c.112G>C	p.Ala38Pro	missense	Exon 4 of 4	ENSP00000515301.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.14
DANN	Benign	0.74
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.20	N
PhyloP100		-2.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.20
Sift	Benign	0.18	T
Sift4G	Benign	0.17	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.17		Gain of relative solvent accessibility (P = 0.0082)
MVP		0.61
MPC		0.47
ClinPred		0.088	T
GERP RS		-8.9
PromoterAI		0.042	Neutral
Varity_R		0.087
gMVP		0.11
Mutation Taster		=89/11	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: rs782239006; hg19: chrX-49114851;