Genetic Variant NM_014009.4:c.1271G>A (chrX-49251359-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_014009.4(FOXP3):c.1271G>A(p.Cys424Tyr) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 22)

Consequence

FOXP3
NM_014009.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 0.0570

Publications

1 publications found

Variant links:

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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

FOXP3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant X-49251359-C-T is Pathogenic according to our data. Variant chrX-49251359-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2584421.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014009.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP3	NM_014009.4	MANE Select	c.1271G>A	p.Cys424Tyr	missense	Exon 12 of 12	NP_054728.2
	FOXP3	NM_001114377.2		c.1166G>A	p.Cys389Tyr	missense	Exon 11 of 11	NP_001107849.1	Q9BZS1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOXP3	ENST00000376207.10	TSL:1 MANE Select	c.1271G>A	p.Cys424Tyr	missense	Exon 12 of 12	ENSP00000365380.4	Q9BZS1-1
FOXP3	ENST00000518685.6	TSL:1	c.1190G>A	p.Cys397Tyr	missense	Exon 10 of 10	ENSP00000428952.2	Q9BZS1-4
FOXP3	ENST00000557224.6	TSL:2	c.1346G>A	p.Cys449Tyr	missense	Exon 10 of 10	ENSP00000451208.1	Q9BZS1-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Insulin-dependent diabetes mellitus secretory diarrhea syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.22

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

-1.0

PhyloP100

0.057

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.014

Polyphen

0.0

Vest4

0.12

MutPred

0.14

Gain of phosphorylation at C424 (P = 0.0241)

MVP

0.99

MPC

0.63

ClinPred

0.21

GERP RS

3.6

Varity_R

0.46

gMVP

0.63

Mutation Taster

=5/95

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.57

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.57

Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over