X-80022300-T-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_001109878.2(TBX22):c.31T>A(p.Ser11Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000165 in 1,209,275 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000014 ( 0 hom. 3 hem. )

Consequence

TBX22
NM_001109878.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.74

Variant links:

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]

TBX22 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000045 (5/111077) while in subpopulation AFR AF= 0.000164 (5/30458). AF 95% confidence interval is 0.0000642. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX22	NM_001109878.2 link	c.31T>A	p.Ser11Thr	missense_variant	Exon 2 of 9	ENST00000373296.8	NP_001103348.1	Q9Y458-1B3KUL8
TBX22	NM_016954.2 link	c.31T>A	p.Ser11Thr	missense_variant	Exon 1 of 8		NP_058650.1	Q9Y458-1
TBX22	NM_001109879.2 link	c.-326T>A		5_prime_UTR_variant	Exon 2 of 9		NP_001103349.1	Q9Y458-2B3KUL8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBX22	ENST00000373296.8 link	c.31T>A	p.Ser11Thr	missense_variant	Exon 2 of 9	5	NM_001109878.2	ENSP00000362393.3	Q9Y458-1
TBX22	ENST00000373294.8 link	c.31T>A	p.Ser11Thr	missense_variant	Exon 1 of 8	1		ENSP00000362390.5	Q9Y458-1
TBX22	ENST00000476373.1 link	n.152T>A		non_coding_transcript_exon_variant	Exon 2 of 2	3
TBX22	ENST00000626498.2 link	n.31T>A		non_coding_transcript_exon_variant	Exon 2 of 9	2		ENSP00000487527.1	A0A0D9SGI2

Frequencies

GnomAD3 genomes

AF:

0.0000450

AC:

AN:

111077

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

33293

show subpopulations

Gnomad AFR

AF:

0.000164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183165

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67663

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1098198

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

363564

show subpopulations

Gnomad4 AFR exome

AF:

0.000454

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.0000450

AC:

AN:

111077

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

33293

show subpopulations

Gnomad4 AFR

AF:

0.000164

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.31T>A (p.S11T) alteration is located in exon 2 (coding exon 1) of the TBX22 gene. This alteration results from a T to A substitution at nucleotide position 31, causing the serine (S) at amino acid position 11 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;T

FATHMM_MKL

Uncertain

0.95

M_CAP

Pathogenic

0.46

MetaRNN

Uncertain

0.52

D;D

MetaSVM

Uncertain

0.75

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.8

N;N

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.99

D;D

Vest4

0.52

MVP

0.76

MPC

0.63

ClinPred

0.46

GERP RS

4.5

Varity_R

0.65

gMVP

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over