chrX-49257557-C-T

Variant names:

• chrX-49257557-C-T
• rs111856931
• NM_014009.4:c.324G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014009.4(FOXP3):​c.324G>A​(p.Thr108Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000405 in 1,186,433 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 102 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., 54 hem., cov: 23)
  • Exomes 𝑓: 0.00021 (0 hom. 48 hem.)
• Consequence: FOXP3 NM_014009.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.48
• 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-49257557-C-T is Benign according to our data. Variant chrX-49257557-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00227 (254/112103) while in subpopulation AFR AF = 0.00783 (241/30783). AF 95% confidence interval is 0.00702. There are 0 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 54 XL gene

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.324G>A	p.Thr108Thr	synonymous	Exon 4 of 12	NP_054728.2
	FOXP3	NM_001114377.2		c.219G>A	p.Thr73Thr	synonymous	Exon 3 of 11	NP_001107849.1	Q9BZS1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXP3	ENST00000376207.10	TSL:1 MANE Select	c.324G>A	p.Thr108Thr	synonymous	Exon 4 of 12	ENSP00000365380.4	Q9BZS1-1
	FOXP3	ENST00000518685.6	TSL:1	c.324G>A	p.Thr108Thr	synonymous	Exon 3 of 10	ENSP00000428952.2	Q9BZS1-4
	FOXP3	ENST00000557224.6	TSL:2	c.219G>A	p.Thr73Thr	synonymous	Exon 3 of 10	ENSP00000451208.1	Q9BZS1-3

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 248 AN: 112051 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00765

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000751

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000565

Gnomad OTH AF: 0.00133

GnomAD2 exomes AF: 0.000646 AC: 103 AN: 159455 AF XY: 0.000382

Gnomad AFR exome AF: 0.00762

Gnomad AMR exome AF: 0.000195

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000741

Gnomad NFE exome AF: 0.0000285

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000210 AC: 226 AN: 1074330 Hom.: 0 Cov.: 32 AF XY: 0.000139 AC XY: 48 AN XY: 346556

African (AFR) AF: 0.00695 AC: 181 AN: 26055

American (AMR) AF: 0.000235 AC: 8 AN: 34038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18204

East Asian (EAS) AF: 0.0000336 AC: 1 AN: 29762

South Asian (SAS) AF: 0.0000391 AC: 2 AN: 51198

European-Finnish (FIN) AF: 0.0000504 AC: 2 AN: 39692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4011

European-Non Finnish (NFE) AF: 0.00000605 AC: 5 AN: 826385

Other (OTH) AF: 0.000600 AC: 27 AN: 44985

GnomAD4 genome AF: 0.00227 AC: 254 AN: 112103 Hom.: 0 Cov.: 23 AF XY: 0.00157 AC XY: 54 AN XY: 34305

African (AFR) AF: 0.00783 AC: 241 AN: 30783

American (AMR) AF: 0.000750 AC: 8 AN: 10660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.00 AC: 0 AN: 2728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000565 AC: 3 AN: 53115

Other (OTH) AF: 0.00131 AC: 2 AN: 1527

Alfa AF: 0.00135 Hom.: 2

Bravo AF: 0.00241

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Insulin-dependent diabetes mellitus secretory diarrhea syndrome (2)
-	-	2	not specified (2)
-	-	1	FOXP3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.6
DANN	Benign	0.74
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs111856931; hg19: chrX-49114014;