rs200060292

Positions:

chrX-80025598-T-A

Variant summary

Our verdict is Benign. Variant got -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

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 links:

TBX22 (HGNC:):

TBX22 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

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

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000308 (337/1093233) while in subpopulation MID AF= 0.00534 (22/4118). AF 95% confidence interval is 0.00362. There are 0 homozygotes in gnomad4_exome. There are 108 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. 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	MANE	Protein	UniProt
TBX22	NM_001109878.2 linkuse as main transcript	c.459-5T>A	splice_region_variant, intron_variant	ENST00000373296.8	NP_001103348.1	Q9Y458-1B3KUL8
TBX22	NM_016954.2 linkuse as main transcript	c.459-5T>A	splice_region_variant, intron_variant		NP_058650.1	Q9Y458-1
TBX22	NM_001109879.2 linkuse as main transcript	c.99-5T>A	splice_region_variant, intron_variant		NP_001103349.1	Q9Y458-2B3KUL8
TBX22	NM_001303475.1 linkuse as main transcript	c.99-5T>A	splice_region_variant, intron_variant		NP_001290404.1	Q9Y458-2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
TBX22	ENST00000373296.8 linkuse as main transcript	c.459-5T>A	splice_region_variant, intron_variant	5	NM_001109878.2	ENSP00000362393.3	Q9Y458-1
TBX22	ENST00000373294.8 linkuse as main transcript	c.459-5T>A	splice_region_variant, intron_variant	1		ENSP00000362390.5	Q9Y458-1
TBX22	ENST00000626877.1 linkuse as main transcript	n.338-5T>A	splice_region_variant, intron_variant	1
TBX22	ENST00000626498.2 linkuse as main transcript	n.*71-5T>A	splice_region_variant, intron_variant	2		ENSP00000487527.1	A0A0D9SGI2

Frequencies

GnomAD3 genomes

AF:

0.000188

AC:

AN:

111699

Hom.:

Cov.:

AF XY:

0.000207

AC XY:

AN XY:

33857

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

GnomAD3 exomes

AF:

0.000203

AC:

AN:

182657

Hom.:

AF XY:

0.000282

AC XY:

AN XY:

67285

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 SAS exome

AF:

0.000157

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

Gnomad4 AFR exome

AF:

0.000608

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000111

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000315

Gnomad4 OTH exome

AF:

0.000632

GnomAD4 genome

AF:

0.000188

AC:

AN:

111699

Hom.:

Cov.:

AF XY:

0.000207

AC XY:

AN XY:

33857

show subpopulations

Gnomad4 AFR

AF:

0.0000326

Gnomad4 AMR

AF:

0.0000947

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000320

Gnomad4 OTH

AF:

0.00136

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2013

- -

Cleft palate with or without ankyloglossia, X-linked

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Aug 06, 2021

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 22, 2015

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

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

DANN

Benign

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over