X-49251345-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_014009.4(FOXP3):c.1285C>T(p.Pro429Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,095,789 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000016 (0 hom. 7 hem.)
• Consequence: FOXP3 NM_014009.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.21

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20914257).
• BP6: Variant X-49251345-G-A is Benign according to our data. Variant chrX-49251345-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2101212.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP3	NM_014009.4	c.1285C>T	p.Pro429Ser	missense_variant	12/12	ENST00000376207.10
FOXP3	NM_001114377.2	c.1180C>T	p.Pro394Ser	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP3	ENST00000376207.10	c.1285C>T	p.Pro429Ser	missense_variant	12/12	1	NM_014009.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000457 AC: 8 AN: 175005 Hom.: 0 AF XY: 0.0000496 AC XY: 3 AN XY: 60541

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 SAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000907

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 18 AN: 1095789 Hom.: 0 Cov.: 31 AF XY: 0.0000194 AC XY: 7 AN XY: 361465

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000932

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000155

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.;T;.;.;.
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.83	T;T;T;T;.;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.21	T;T;T;T;T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.1	L;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.52	N;N;.;N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0050	D;D;.;D;D;D
Sift4G	Benign	0.39	T;D;T;T;D;T
Polyphen		1.0	D;D;D;P;D;.
Vest4		0.27
MutPred		0.20		Gain of phosphorylation at P429 (P = 0.018);.;.;.;.;.;
MVP		0.85
MPC		0.52
ClinPred		0.13	T
GERP RS		2.7
Varity_R		0.061
gMVP		0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs782088695; hg19: chrX-49107806;