X-49258476-C-A

Variant names:

• chrX-49258476-C-A
• rs142994383
• NM_014009.4:c.30G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_014009.4(FOXP3):​c.30G>T​(p.Ser10Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000938 in 1,066,635 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S10S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: FOXP3 NM_014009.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• Publications: 0 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP7: Synonymous conserved (PhyloP=-1.28 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXP3	NM_014009.4	c.30G>T	p.Ser10Ser	synonymous_variant	Exon 2 of 12	ENST00000376207.10	NP_054728.2
FOXP3	NM_001114377.2	c.30G>T	p.Ser10Ser	synonymous_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.30G>T	p.Ser10Ser	synonymous_variant	Exon 2 of 12	1	NM_014009.4	ENSP00000365380.4
ENSG00000290184	ENST00000703450.1	c.30G>T	p.Ser10Ser	synonymous_variant	Exon 4 of 4			ENSP00000515301.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.38e-7 AC: 1 AN: 1066635 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 341803

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000388 AC: 1 AN: 25747

American (AMR) AF: 0.00 AC: 0 AN: 30866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18359

East Asian (EAS) AF: 0.00 AC: 0 AN: 29222

South Asian (SAS) AF: 0.00 AC: 0 AN: 49914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3944

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 825548

Other (OTH) AF: 0.00 AC: 0 AN: 44693

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.3
DANN	Benign	0.59
PhyloP100		-1.3
PromoterAI		-0.019	Neutral

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: rs142994383; hg19: chrX-49114933;