chrX-49258330-G-T

Variant names:

• chrX-49258330-G-T
• rs199917616
• NM_014009.4:c.176C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014009.4(FOXP3):​c.176C>A​(p.Ser59Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. S59C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: FOXP3 NM_014009.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.46
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP3	NM_014009.4	c.176C>A	p.Ser59Tyr	missense_variant	Exon 2 of 12	ENST00000376207.10	NP_054728.2
FOXP3	NM_001114377.2	c.176C>A	p.Ser59Tyr	missense_variant	Exon 2 of 11		NP_001107849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP3	ENST00000376207.10	c.176C>A	p.Ser59Tyr	missense_variant	Exon 2 of 12	1	NM_014009.4	ENSP00000365380.4
ENSG00000290184	ENST00000703450.1	c.*13C>A		downstream_gene_variant				ENSP00000515301.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;T;.;.;.
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.85	D;D;D;D;.;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.50	D;D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	0.97	L;L;.;L;L;.
PhyloP100		4.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.039	D;D;D;D;D;D
Polyphen		0.13	B;B;D;B;B;.
Vest4		0.35
MutPred		0.35		Gain of catalytic residue at S59 (P = 0.0067);Gain of catalytic residue at S59 (P = 0.0067);Gain of catalytic residue at S59 (P = 0.0067);Gain of catalytic residue at S59 (P = 0.0067);Gain of catalytic residue at S59 (P = 0.0067);.;
MVP		0.91
MPC		1.3
ClinPred		0.89	D
GERP RS		4.3
PromoterAI		-0.089	Neutral
Varity_R		0.23
gMVP		0.35
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199917616; hg19: chrX-49114787;