rs55760411

Positions:

• chrX-80023047-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001109878.2(TBX22):​c.176-13C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00628 in 1,208,342 control chromosomes in the GnomAD database, including 24 homozygotes. There are 2,345 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 0.0044 (0 hom., 139 hem., cov: 22)
  • Exomes 𝑓: 0.0065 (24 hom. 2206 hem.)
• Consequence: TBX22 NM_001109878.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.27

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-80023047-C-A is Benign according to our data. Variant chrX-80023047-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 445911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-80023047-C-A is described in Lovd as [Benign]. Variant chrX-80023047-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0044 (489/111228) while in subpopulation NFE AF= 0.00779 (413/53014). AF 95% confidence interval is 0.00717. There are 0 homozygotes in gnomad4. There are 139 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 139 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX22	NM_001109878.2	c.176-13C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000373296.8	NP_001103348.1
TBX22	NM_001109879.2	c.-181-13C>A		splice_polypyrimidine_tract_variant, intron_variant			NP_001103349.1
TBX22	NM_016954.2	c.176-13C>A		splice_polypyrimidine_tract_variant, intron_variant			NP_058650.1
TBX22	NM_001303475.1			upstream_gene_variant			NP_001290404.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX22	ENST00000373296.8	c.176-13C>A		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001109878.2	ENSP00000362393	P1
TBX22	ENST00000373294.8	c.176-13C>A		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000362390	P1
TBX22	ENST00000626498.2	c.176-13C>A		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2		ENSP00000487527
TBX22	ENST00000626877.1			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.00441 AC: 490 AN: 111175 Hom.: 0 Cov.: 22 AF XY: 0.00417 AC XY: 139 AN XY: 33349

Gnomad AFR AF: 0.000721

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000762

Gnomad ASJ AF: 0.000379

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00193

Gnomad FIN AF: 0.00600

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00779

Gnomad OTH AF: 0.00134

GnomAD3 exomes AF: 0.00445 AC: 807 AN: 181147 Hom.: 2 AF XY: 0.00437 AC XY: 287 AN XY: 65747

Gnomad AFR exome AF: 0.000384

Gnomad AMR exome AF: 0.000293

Gnomad ASJ exome AF: 0.000403

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00165

Gnomad FIN exome AF: 0.00592

Gnomad NFE exome AF: 0.00796

Gnomad OTH exome AF: 0.00556

GnomAD4 exome AF: 0.00647 AC: 7100 AN: 1097114 Hom.: 24 Cov.: 31 AF XY: 0.00608 AC XY: 2206 AN XY: 362558

Gnomad4 AFR exome AF: 0.000606

Gnomad4 AMR exome AF: 0.000398

Gnomad4 ASJ exome AF: 0.000465

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00178

Gnomad4 FIN exome AF: 0.00726

Gnomad4 NFE exome AF: 0.00765

Gnomad4 OTH exome AF: 0.00508

GnomAD4 genome AF: 0.00440 AC: 489 AN: 111228 Hom.: 0 Cov.: 22 AF XY: 0.00416 AC XY: 139 AN XY: 33412

Gnomad4 AFR AF: 0.000720

Gnomad4 AMR AF: 0.000762

Gnomad4 ASJ AF: 0.000379

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00155

Gnomad4 FIN AF: 0.00600

Gnomad4 NFE AF: 0.00779

Gnomad4 OTH AF: 0.00132

Alfa AF: 0.00660 Hom.: 171

Bravo AF: 0.00360

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cleft palate with or without ankyloglossia, X-linked Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 18, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	TBX22: BS1 -

TBX22-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.9
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs55760411; hg19: chrX-79278546;