X-80022261-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.-2-7C>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 0.00107 in 1,208,650 control chromosomes in the GnomAD database, including 12 homozygotes. There are 364 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (7 hom., 158 hem., cov: 22)
  • Exomes 𝑓: 0.00065 (5 hom. 206 hem.)
• Consequence: TBX22 NM_001109878.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003026
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0620

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=-0.78).
• BP6: Variant X-80022261-C-A is Benign according to our data. Variant chrX-80022261-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 368663.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 = 0.00531 (588/110796) while in subpopulation AFR AF= 0.018 (548/30429). AF 95% confidence interval is 0.0168. There are 7 homozygotes in gnomad4. There are 158 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX22	NM_001109878.2	c.-2-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000373296.8
TBX22	NM_016954.2	c.-9C>A		5_prime_UTR_variant	1/8
TBX22	NM_001109879.2	c.-358-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX22	ENST00000373294.8	c.-9C>A		5_prime_UTR_variant	1/8	1		P1
TBX22	ENST00000373296.8	c.-2-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001109878.2	P1
TBX22	ENST00000626498.2	c.-2-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2
TBX22	ENST00000476373.1	n.120-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00530 AC: 587 AN: 110748 Hom.: 7 Cov.: 22 AF XY: 0.00476 AC XY: 157 AN XY: 32976

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00277

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: 0.0000946

Gnomad OTH AF: 0.00406

GnomAD3 exomes AF: 0.00191 AC: 348 AN: 182524 Hom.: 5 AF XY: 0.00136 AC XY: 91 AN XY: 67144

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.00248

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000941

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000984

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000647 AC: 710 AN: 1097854 Hom.: 5 Cov.: 31 AF XY: 0.000567 AC XY: 206 AN XY: 363222

Gnomad4 AFR exome AF: 0.0175

Gnomad4 AMR exome AF: 0.00250

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000431

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000950

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00531 AC: 588 AN: 110796 Hom.: 7 Cov.: 22 AF XY: 0.00478 AC XY: 158 AN XY: 33034

Gnomad4 AFR AF: 0.0180

Gnomad4 AMR AF: 0.00277

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000946

Gnomad4 OTH AF: 0.00401

Alfa AF: 0.000174 Hom.: 1

Bravo AF: 0.00633

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TBX22-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2020

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

Cleft palate with or without ankyloglossia, X-linked Benign:1

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	8.1
Dann	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -38

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

Publications

LitVar

Other links and lift over

dbSNP: rs185298778; hg19: chrX-79277760;