X-80022261-C-G

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>G 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 0.000867 in 1,208,653 control chromosomes in the GnomAD database, including 6 homozygotes. There are 283 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (2 hom., 120 hem., cov: 22)
  • Exomes 𝑓: 0.00052 (4 hom. 163 hem.)
• Consequence: TBX22 NM_001109878.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003026
• Clinical Significance: 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=-0.81).
• BP6: Variant X-80022261-C-G is Benign according to our data. Variant chrX-80022261-C-G is described in ClinVar as [Benign]. Clinvar id is 804041.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 = 0.0043 (476/110797) while in subpopulation AFR AF= 0.015 (457/30430). AF 95% confidence interval is 0.0139. There are 2 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX22	NM_001109878.2	c.-2-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000373296.8
TBX22	NM_016954.2	c.-9C>G		5_prime_UTR_variant	1/8
TBX22	NM_001109879.2	c.-358-7C>G		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>G		5_prime_UTR_variant	1/8	1		P1
TBX22	ENST00000373296.8	c.-2-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001109878.2	P1
TBX22	ENST00000626498.2	c.-2-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2
TBX22	ENST00000476373.1	n.120-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00429 AC: 475 AN: 110749 Hom.: 2 Cov.: 22 AF XY: 0.00361 AC XY: 119 AN XY: 32977

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

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: 0.0000567

Gnomad OTH AF: 0.00203

GnomAD3 exomes AF: 0.00142 AC: 260 AN: 182524 Hom.: 2 AF XY: 0.00106 AC XY: 71 AN XY: 67144

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.000767

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.000521 AC: 572 AN: 1097856 Hom.: 4 Cov.: 31 AF XY: 0.000449 AC XY: 163 AN XY: 363222

Gnomad4 AFR exome AF: 0.0173

Gnomad4 AMR exome AF: 0.000767

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000154

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00430 AC: 476 AN: 110797 Hom.: 2 Cov.: 22 AF XY: 0.00363 AC XY: 120 AN XY: 33035

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000567

Gnomad4 OTH AF: 0.00200

Alfa AF: 0.000305 Hom.: 1

Bravo AF: 0.00531

ClinVar

Significance: 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

Aug 15, 2019

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

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	9.4
Dann	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.31		Position offset: -33
DS_AL_spliceai		0.37		Position offset: 7

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; COSMIC: COSV104681225; COSMIC: COSV104681225;