X-49251389-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4 BP6_Very_Strong BS2

The NM_014009.4(FOXP3):c.1241G>A(p.Arg414His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,209,860 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 42 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R414C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.00013 (0 hom. 41 hem.)
• Consequence: FOXP3 NM_014009.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.49

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 -11 ACMG points.

• PM1: In a DNA_binding_region Fork-head (size 86) in uniprot entity FOXP3_HUMAN there are 22 pathogenic changes around while only 3 benign (88%) in NM_014009.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.27564973).
• BP6: Variant X-49251389-C-T is Benign according to our data. Variant chrX-49251389-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 763524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXP3	NM_014009.4	c.1241G>A	p.Arg414His	missense_variant	12/12	ENST00000376207.10
FOXP3	NM_001114377.2	c.1136G>A	p.Arg379His	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXP3	ENST00000376207.10	c.1241G>A	p.Arg414His	missense_variant	12/12	1	NM_014009.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000534 AC: 6 AN: 112316 Hom.: 0 Cov.: 22 AF XY: 0.0000290 AC XY: 1 AN XY: 34476

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000279

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000940

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000664 AC: 12 AN: 180641 Hom.: 0 AF XY: 0.0000916 AC XY: 6 AN XY: 65497

Gnomad AFR exome AF: 0.000155

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000145

Gnomad SAS exome AF: 0.000107

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000745

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000129 AC: 142 AN: 1097544 Hom.: 0 Cov.: 31 AF XY: 0.000113 AC XY: 41 AN XY: 362950

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000663

Gnomad4 SAS exome AF: 0.0000556

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000160

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000534 AC: 6 AN: 112316 Hom.: 0 Cov.: 22 AF XY: 0.0000290 AC XY: 1 AN XY: 34476

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000279

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000940

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Insulin-dependent diabetes mellitus secretory diarrhea syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	23
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D;.;T;.;.;.
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.97	D;D;D;D;.;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.28	T;T;T;T;T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.2	L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.0	N;N;.;N;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.095	T;T;.;T;T;T
Sift4G	Benign	0.11	T;T;T;T;T;T
Polyphen		1.0	D;D;D;P;D;.
Vest4		0.12
MVP		0.96
MPC		1.3
ClinPred		0.19	T
GERP RS		4.6
Varity_R		0.24
gMVP		0.84

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: rs782786757; hg19: chrX-49107850; COSMIC: COSV66051211; COSMIC: COSV66051211;