chrX-80022325-C-A

Position:

chrX-80022325-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001109878.2(TBX22):c.56C>A(p.Pro19His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,209,284 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000012 ( 0 hom. 7 hem. )

Consequence

TBX22
NM_001109878.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.95

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16090599).

BS2

High Hemizygotes in GnomAdExome4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TBX22	NM_001109878.2 linkuse as main transcript	c.56C>A	p.Pro19His	missense_variant	2/9	ENST00000373296.8	NP_001103348.1
TBX22	NM_016954.2 linkuse as main transcript	c.56C>A	p.Pro19His	missense_variant	1/8		NP_058650.1
TBX22	NM_001109879.2 linkuse as main transcript	c.-301C>A		5_prime_UTR_variant	2/9		NP_001103349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX22	ENST00000373296.8 linkuse as main transcript	c.56C>A	p.Pro19His	missense_variant	2/9	5	NM_001109878.2	ENSP00000362393	P1	Q9Y458-1
TBX22	ENST00000373294.8 linkuse as main transcript	c.56C>A	p.Pro19His	missense_variant	1/8	1		ENSP00000362390	P1	Q9Y458-1
TBX22	ENST00000476373.1 linkuse as main transcript	n.177C>A		non_coding_transcript_exon_variant	2/2	3
TBX22	ENST00000626498.2 linkuse as main transcript	c.56C>A	p.Pro19His	missense_variant, NMD_transcript_variant	2/9	2		ENSP00000487527

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111241

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33469

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000573

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:

0.0000328

AC:

AN:

183038

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

67546

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000434

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:

0.0000118

AC:

AN:

1098043

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

363405

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000397

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111241

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33469

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000573

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2024

The c.56C>A (p.P19H) alteration is located in exon 2 (coding exon 1) of the TBX22 gene. This alteration results from a C to A substitution at nucleotide position 56, causing the proline (P) at amino acid position 19 to be replaced by a histidine (H). 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

0.13

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T

FATHMM_MKL

Benign

0.41

M_CAP

Pathogenic

0.61

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.9

L;L

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.25

Sift

Uncertain

0.018

D;D

Sift4G

Benign

0.072

T;T

Polyphen

0.97

D;D

Vest4

0.33

MutPred

0.21

Loss of glycosylation at P19 (P = 0.025);Loss of glycosylation at P19 (P = 0.025);

MVP

0.52

MPC

0.56

ClinPred

0.22

GERP RS

2.6

Varity_R

0.26

gMVP

0.45

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