X-80022341-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001109878.2(TBX22):c.72C>T(p.Leu24=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,209,470 control chromosomes in the GnomAD database, including 22 homozygotes. There are 545 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (10 hom., 223 hem., cov: 22)
  • Exomes 𝑓: 0.0011 (12 hom. 322 hem.)
• Consequence: TBX22 NM_001109878.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.04

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-80022341-C-T is Benign according to our data. Variant chrX-80022341-C-T is described in ClinVar as [Benign]. Clinvar id is 368664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-80022341-C-T is described in Lovd as [Likely_benign]. Variant chrX-80022341-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00803 (896/111597) while in subpopulation AFR AF= 0.0257 (787/30642). AF 95% confidence interval is 0.0242. There are 10 homozygotes in gnomad4. There are 223 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX22	NM_001109878.2	c.72C>T	p.Leu24=	synonymous_variant	2/9	ENST00000373296.8
TBX22	NM_016954.2	c.72C>T	p.Leu24=	synonymous_variant	1/8
TBX22	NM_001109879.2	c.-285C>T		5_prime_UTR_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX22	ENST00000373296.8	c.72C>T	p.Leu24=	synonymous_variant	2/9	5	NM_001109878.2	P1
TBX22	ENST00000373294.8	c.72C>T	p.Leu24=	synonymous_variant	1/8	1		P1
TBX22	ENST00000476373.1	n.193C>T		non_coding_transcript_exon_variant	2/2	3
TBX22	ENST00000626498.2	c.72C>T	p.Leu24=	synonymous_variant, NMD_transcript_variant	2/9	2

Frequencies

GnomAD3 genomes AF: 0.00792 AC: 883 AN: 111547 Hom.: 10 Cov.: 22 AF XY: 0.00634 AC XY: 214 AN XY: 33769

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00540

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000753

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.00297 AC: 543 AN: 182765 Hom.: 8 AF XY: 0.00202 AC XY: 136 AN XY: 67285

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00847

Gnomad SAS exome AF: 0.000263

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00112 AC: 1230 AN: 1097873 Hom.: 12 Cov.: 31 AF XY: 0.000886 AC XY: 322 AN XY: 363239

Gnomad4 AFR exome AF: 0.0291

Gnomad4 AMR exome AF: 0.00176

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00543

Gnomad4 SAS exome AF: 0.000296

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000368

Gnomad4 OTH exome AF: 0.00395

GnomAD4 genome AF: 0.00803 AC: 896 AN: 111597 Hom.: 10 Cov.: 22 AF XY: 0.00659 AC XY: 223 AN XY: 33829

Gnomad4 AFR AF: 0.0257

Gnomad4 AMR AF: 0.00539

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00773

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000753

Gnomad4 OTH AF: 0.0139

Alfa AF: 0.00494 Hom.: 24

Bravo AF: 0.00936

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.78
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs138387312; hg19: chrX-79277840;