rs200060292

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001109878.2(TBX22):c.459-5T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000297 in 1,204,932 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 115 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., 7 hem., cov: 22)

Exomes 𝑓: 0.00031 ( 0 hom. 108 hem. )

Consequence

TBX22
NM_001109878.2 splice_region, intron

Scores

Splicing: ADA: 0.4644

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 1.80

Publications

2 publications found

Variant links:

Genes affected

TBX22 (HGNC:11600): (T-box transcription factor 22) This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. Mutations in this gene have been associated with the inherited X-linked disorder, Cleft palate with ankyloglossia, and it is believed to play a major role in human palatogenesis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

TBX22 Gene-Disease associations (from GenCC):

cleft palate with or without ankyloglossia, X-linked
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
Abruzzo-Erickson syndrome
Inheritance: XL Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P

TBX22 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000188 (21/111699) while in subpopulation NFE AF = 0.00032 (17/53154). AF 95% confidence interval is 0.000203. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TBX22	NM_001109878.2 link	c.459-5T>A	splice_region_variant, intron_variant	Intron 4 of 8	ENST00000373296.8	NP_001103348.1	Q9Y458-1B3KUL8
TBX22	NM_016954.2 link	c.459-5T>A	splice_region_variant, intron_variant	Intron 3 of 7		NP_058650.1	Q9Y458-1
TBX22	NM_001109879.2 link	c.99-5T>A	splice_region_variant, intron_variant	Intron 4 of 8		NP_001103349.1	Q9Y458-2B3KUL8
TBX22	NM_001303475.1 link	c.99-5T>A	splice_region_variant, intron_variant	Intron 2 of 6		NP_001290404.1	Q9Y458-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBX22	ENST00000373296.8 link	c.459-5T>A	splice_region_variant, intron_variant	Intron 4 of 8	5	NM_001109878.2	ENSP00000362393.3	Q9Y458-1
TBX22	ENST00000373294.8 link	c.459-5T>A	splice_region_variant, intron_variant	Intron 3 of 7	1		ENSP00000362390.5	Q9Y458-1
TBX22	ENST00000626877.1 link	n.338-5T>A	splice_region_variant, intron_variant	Intron 2 of 6	1
TBX22	ENST00000626498.2 link	n.*71-5T>A	splice_region_variant, intron_variant	Intron 4 of 8	2		ENSP00000487527.1	A0A0D9SGI2

Frequencies

GnomAD3 genomes

AF:

0.000188

AC:

AN:

111699

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000947

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:

0.000320

Gnomad OTH

AF:

0.00136

GnomAD2 exomes

AF:

0.000203

AC:

AN:

182657

AF XY:

0.000282

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000369

Gnomad OTH exome

AF:

0.000885

GnomAD4 exome

AF:

0.000308

AC:

337

AN:

1093233

Hom.:

Cov.:

AF XY:

0.000301

AC XY:

108

AN XY:

358781

show subpopulations

African (AFR)

AF:

0.000608

AC:

AN:

26310

American (AMR)

AF:

0.00

AC:

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19355

East Asian (EAS)

AF:

0.00

AC:

AN:

30185

South Asian (SAS)

AF:

0.000111

AC:

AN:

54052

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40497

Middle Eastern (MID)

AF:

0.00534

AC:

AN:

4118

European-Non Finnish (NFE)

AF:

0.000315

AC:

264

AN:

837607

Other (OTH)

AF:

0.000632

AC:

AN:

45908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.000188

AC:

AN:

111699

Hom.:

Cov.:

AF XY:

0.000207

AC XY:

AN XY:

33857

show subpopulations

African (AFR)

AF:

0.0000326

AC:

AN:

30684

American (AMR)

AF:

0.0000947

AC:

AN:

10565

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2655

East Asian (EAS)

AF:

0.00

AC:

AN:

3545

South Asian (SAS)

AF:

0.00

AC:

AN:

2635

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000320

AC:

AN:

53154

Other (OTH)

AF:

0.00136

AC:

AN:

1476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

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:

0.000651

Hom.:

Bravo

AF:

0.000155

EpiCase

AF:

0.000818

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Abruzzo-Erickson syndrome

Pathogenic:1

Apr 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Cleft palate with or without ankyloglossia, X-linked

Pathogenic:1

Aug 06, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Oct 22, 2015

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.459-5T>A variant in the TBX22 gene has been reported previously in a family with CHARGE-like Abruzzoâ€“Erickson syndrome (Pauws et al., 2013). A functional study showed the c.459-5T>A variant almost abolished the wild type splicing product and led to a significant increase in the most upstream cryptic splice site product of exon 4 (Pauws et al., 2013). The c.459-5T>A variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.459-5T>A variant is a strong candidate for a pathogenic variant however the possibility it may be a rare benign variant cannot be excluded. -

not specified

Uncertain:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

1.8

Mutation Taster

=97/3

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.46

dbscSNV1_RF

Benign

0.42

SpliceAI score (max)

0.37

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.37

Position offset: 5

DS_DG_spliceai

0.30

Position offset: 4

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