rs148013438

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014009.4(FOXP3):c.*673G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 281,687 control chromosomes in the GnomAD database, including 16 homozygotes. There are 357 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 0.0086 ( 12 hom., 262 hem., cov: 24)

Exomes 𝑓: 0.0021 ( 4 hom. 95 hem. )

Consequence

FOXP3
NM_014009.4 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.02

Publications

2 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 links:

CCDC22 (HGNC:28909): (coiled-coil domain containing 22) This gene encodes a protein containing a coiled-coil domain. The encoded protein functions in the regulation of NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) by interacting with COMMD (copper metabolism Murr1 domain-containing) proteins. The mouse orthologous protein has been shown to bind copines, which are calcium-dependent, membrane-binding proteins that may function in calcium signaling. This human gene has been identified as a novel candidate gene for syndromic X-linked intellectual disability. [provided by RefSeq, Aug 2013]

CCDC22 Gene-Disease associations (from GenCC):

Ritscher-Schinzel syndrome 2
Inheritance: XL Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
Ritscher-Schinzel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
epilepsy
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

CCDC22 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant X-49250661-C-T is Benign according to our data. Variant chrX-49250661-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 260313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00864 (970/112312) while in subpopulation AFR AF = 0.0276 (853/30901). AF 95% confidence interval is 0.0261. There are 12 homozygotes in GnomAd4. There are 262 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
FOXP3	NM_014009.4 link	c.*673G>A	3_prime_UTR_variant	Exon 12 of 12	ENST00000376207.10	NP_054728.2
FOXP3	NM_001114377.2 link	c.*673G>A	3_prime_UTR_variant	Exon 11 of 11		NP_001107849.1
CCDC22	NM_014008.5 link	c.*400C>T	downstream_gene_variant		ENST00000376227.4	NP_054727.1
CCDC22	XM_005272599.5 link	c.*400C>T	downstream_gene_variant			XP_005272656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXP3	ENST00000376207.10 link	c.*673G>A		3_prime_UTR_variant	Exon 12 of 12	1	NM_014009.4	ENSP00000365380.4
CCDC22	ENST00000376227.4 link	c.*400C>T		downstream_gene_variant		1	NM_014008.5	ENSP00000365401.3

Frequencies

GnomAD3 genomes

AF:

0.00860

AC:

965

AN:

112258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0275

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00357

Gnomad ASJ

AF:

0.000378

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000368

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0333

Gnomad NFE

AF:

0.000940

Gnomad OTH

AF:

0.0125

GnomAD4 exome

AF:

0.00210

AC:

355

AN:

169375

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

AN XY:

56069

show subpopulations

African (AFR)

AF:

0.0299

AC:

156

AN:

5213

American (AMR)

AF:

0.00370

AC:

AN:

10267

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4352

East Asian (EAS)

AF:

0.000129

AC:

AN:

7750

South Asian (SAS)

AF:

0.000154

AC:

AN:

25964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8054

Middle Eastern (MID)

AF:

0.0159

AC:

AN:

878

European-Non Finnish (NFE)

AF:

0.00105

AC:

103

AN:

98038

Other (OTH)

AF:

0.00440

AC:

AN:

8859

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00864

AC:

970

AN:

112312

Hom.:

Cov.:

AF XY:

0.00759

AC XY:

262

AN XY:

34518

show subpopulations

African (AFR)

AF:

0.0276

AC:

853

AN:

30901

American (AMR)

AF:

0.00356

AC:

AN:

10663

Ashkenazi Jewish (ASJ)

AF:

0.000378

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3566

South Asian (SAS)

AF:

0.000369

AC:

AN:

2709

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6201

Middle Eastern (MID)

AF:

0.0365

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000940

AC:

AN:

53191

Other (OTH)

AF:

0.0124

AC:

AN:

1533

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00664

Hom.:

Bravo

AF:

0.0102

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.034

(source)

DANN

Benign

0.78

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over