rs200060292

chrX-80025598-T-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001109878.2(TBX22):c.459-5T>A variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.4644
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 1.80

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]

ACMG classification

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 GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX22	NM_001109878.2	c.459-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000373296.8
TBX22	NM_001109879.2	c.99-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
TBX22	NM_001303475.1	c.99-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
TBX22	NM_016954.2	c.459-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX22	ENST00000373296.8	c.459-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001109878.2	P1
TBX22	ENST00000373294.8	c.459-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
TBX22	ENST00000626877.1	n.338-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
TBX22	ENST00000626498.2	c.*71-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000188 AC: 21 AN: 111699 Hom.: 0 Cov.: 22 AF XY: 0.000207 AC XY: 7 AN XY: 33857

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: 37 AN: 182657 Hom.: 0 AF XY: 0.000282 AC XY: 19 AN XY: 67285

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.: 0 Cov.: 29 AF XY: 0.000301 AC XY: 108 AN XY: 358781

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: 21 AN: 111699 Hom.: 0 Cov.: 22 AF XY: 0.000207 AC XY: 7 AN XY: 33857

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.: 4

Bravo AF: 0.000155

EpiCase AF: 0.000818

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

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 Abruzzo–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	16
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

Other links and lift over

dbSNP: rs200060292; hg19: chrX-79281097;